Triazolopyridazine compounds, their production and use

ABSTRACT

Novel compound represented by the formula: ##STR1## wherein R 1  stands for H, an optionally substituted lower alkyl group or a halogen; R 2  and R 3  respectively stands for a hydrogen or an optionally substituted lower alkyl group, or R 2  and R 3  may, taken together with the adjacent --C═C-- group, form a 5- to 7-membered ring; X stands for O, SO or SO 2  ; Y stands for a group of the formula: ##STR2## (R 4  and R 5  respectively stand for H or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R 6  and R 7  each stands for H, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6  and R 7  may, taken together with the adjacent N, form an optionally substituted N-containing heterocyclic group; m stands for 0 to 4; n stands for 0 to 4, or a salt thereof, which has excellent anti-PAF activities anti-LTC 4  activities and anti-ET-1 activities, and is of value as an antiasthmatic agent, and their production, intermediates and pharmasceutical compositions.

The present invention relates to triazolopyridazine derivatives andtheir salts, their production, intermediates, and pharmaceuticalcompositions. The triazolopyridazine derivative and its salt of thepresent invention have antiallergic, antiinflammatory and anti-PAF(platelet activating factor) activities and, by virtue of theirinhibitory action on bronchospasm and bronchoconstriction, can be usedas effective antiasthmatic agents.

While a large number of triazolopyridazine compounds are synthesized oflate for use as drugs effective against a variety of diseases, U.S. Pat.No. 3,915,968 discloses a compound of the formula: ##STR3## wherein Rand R³ independently stand for a hydrogen atom or a lower alkyl group(at least one of R and R³ is lower alkyl); R¹ and R², taken togetherwith the nitrogen atom, stand for a heterocyclic group selected fromamong pyrrolidine, piperidine, piperazine and morpholine, or a saltthereof;

U.S. Pat. No. 4,136,182 discloses a compound of the formula: ##STR4##wherein R stand for hydrogen, phenyl or lower alkylcarbonylamino; R¹stands for morpholino or piperidino; R² means hydrogen or lower alkyl;provided, however, that at least one of R and R² is a species other thanhydrogen and further that when R is phenyl, R¹ stands for morpholino andR² stands for lower alkyl, or a salt thereof; EP-A-0 248 413 describes acompound of the formula: ##STR5## or a salt thereof, all noting to theeffect that the respective compounds are of use as bronchodilatorseffective for relief of bronchospasms.

Although a wide variety of antiasthmatic drugs are now commerciallyavailable, none are satisfactory as to action sustainability, safety andother properties. It is therefore desired that a new compound bedeveloped which exhibits more antiallergic, anti-inflammatory andanti-PAF activities and which is excellent in action sustainability,safety and other properties for an antiasthmatic drug.

The present inventors investigated the chemical modefication of[1,2,4]triazolo[1,5-b]pyridazine compounds at the 6 position, and foundthat a new series of [1,2,4]triazolo[1,5-b]pyridazine compoundsstructurally different from the above-mentioned known compoundsunexpectedly exhibited highly antiallergic, anti-inflammatory andanti-PAF activities and excellent action substainability and safety.They further found that these compounds inhibit bronchospasm andbronchoconstriction and, therefore, could be utilized as effectiveantiasthmatic agents. Based on these findings, the present invention hasbeen accomplished.

Thus, the present invention provides

(1) a compound of the general formula: ##STR6## wherein R¹ stands for ahydrogen atom, an optionally substituted lower alkyl group or a halogenatom; R² and R³ each stands for a hydrogen atom or an optionallysubstituted lower alkyl group, or R² and R³ may, taken together with theadjacent --C═C-- group, form a 5- to 7-membered ring; X stands for anoxygen atom or S(O)_(p) (p stands for a whole number of 0 to 2); Ystands for a group of the formula: ##STR7## (R⁴ and R⁵ each is ahydrogen atom or an optionally substituted lower alkyl group) or adivalent group derived from an optionally substituted 3- to 7-memberedhomocyclic or heterocyclic ring; R⁶ and R⁷ each stands for a hydrogenatom, an optionally substituted lower alkyl group, an optionallysubstituted cycloalkyl group or an optionally substituted aryl group, orR⁶ and R⁷ may, taken together with the adjacent nitrogen atom, form anoptionally substituted nitrogen-containing heterocyclic group; m standsfor a whole number of 0 to 4; n stands for a whole number of 0 to 4, ora salt thereof,

(2) a process for producing a compound described above in (1) whichcomprises reacting a compound of the general formula: ##STR8## whereinZ¹ means a reactive group; R¹, R² and R³ are as defined above, or a saltthereof with a compound of the general formula: ##STR9## wherein Z²means a group which leaves on reacting with Z¹ ; X, Y, R⁶, R⁷, m and nare as defined above, or a salt thereof,

(3) a process for producing a compound described above in (1) whichcomprises reacting a compound of the general formula: ##STR10## whereinZ², R¹, R², R³ and X are as defined above, or a salt thereof with acompound of the general formula: ##STR11## wherein Z¹, Y, R⁶, R⁷, m andn are as defined above, or a salt thereof,

(4) a process for producing a compound described above in (1) whichcomprises reacting a compound of the general formula: ##STR12## whereinW means a leaving group; R¹, R², R³, X, Y, m and n are as defined above,or a salt thereof with a compound of the general formula: ##STR13##wherein R⁶ and R⁷ are as defined above, or a salt thereof,

(5) an antiasthmatic composition characterized by containing thecompound [I] or a salt thereof,

(6) an anti-PAF composition characterized by containing the compound [I]or a salt thereof,

(7) the compound [VI] or a salt thereof.

It should be understood that where the compound [I] or a salt thereofcontains asymmetric carbon within its structure, it may occur asoptically active isomers as well as racemic mixtures and that theseisomers and mixtures also fall within the scope of the invention.

As used throughout this specification, the term `lower alkyl` meansinter alia a straight-chain or branched C₁₋₆ alkyl group. The C₁₋₆ alkylgroup includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,tert-butyl, n-pentyl, n-hexyl and so on.

The term `cycloalkyl` means inter alia a C₃₋₆ cycloalkyl group. The C₃₋₆cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term `aryl` means inter alia a C₆₋₁₄ aryl group. The C₆₋₁₄ arylgroup includes phenyl, naphthyl and so on.

Substituent group(s) by which said `lower alkyl` and `cycloalkyl` mayoptionally be substituted, may range from 1 to 4 in number and areselected from among hydroxy, amino, carboxyl, nitro, mono- or di-loweralkylamino (e.g. mono- or di-C₁₋₆ alkylamino groups such as methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.), loweralkoxy (e.g. C₁₋₆ alkoxy groups such as methoxy, ethoxy, propoxy,hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C₁₋₆ alkylcarbonyloxygroups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine,chlorine, bromine and iodine) and so on.

Substituent group(s) by which said `aryl` group may optionally besubstituted, may range from 1 to 5 in number and are selected from amongoptionally substituted lower alkyl, optionally substituted amino,acetamido, hydroxy, carboxyl, nitro, lower alkoxy (e.g. C₁₋₆ alkoxygroups such as methoxy, ethoxy, propoxy, etc.), lower alkylcarbonyloxy(e.g. C₁₋₆ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy,etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine) andso on. In this connection, substituent group(s) by which the lower alkyl(e.g. C₁₋₆ alkyl group such as methyl, ethyl, n-propyl, etc.) mentionedjust above may be substituted, may range from 1 to 4 in number and areselected from among hydroxy, amino, mono- or di-lower alkylamino (e.g.mono- or di-C₁₋₆ alkylamino groups such as methylamino, ethylamino,propylamino, dimethylamino, diethylamino, etc.), lower alkoxy (e.g. C₁₋₆alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), halogen(e.g. fluorine, chlorine, bromine and iodine) and so on. Substituentgroup(s) by which the amino group mentioned above may be substituted,may range from 1 to 2 in number and are selected from among C₁₋₆ alkyl(e.g. methyl, ethyl, propyl, etc.), 5- to 7-membered cyclic amino (e.g.pyrrolidino, morpholino, piperidino, piperazino, etc.) and so on.

The term `halogen` means fluorine, chlorine, bromine or iodine, forinstance.

The `5- to 7-membered ring formed in combination with the adjacent--C═C-- group` means a 5- to 7-membered ring such as, for example, ringswhich may contain 1 to 4 hetero-atoms selected from among nitrogen,oxygen, sulfur, etc. in addition to carbon atoms. Thus, in particular,5- to 7-membered hydrocarbon rings, e.g. C₅₋₇ cycloalkenes such ascyclopentene, cyclohexene, cycloheptene, etc., benzene and so on and a5- or 6-membered nitrogen-containing heterocyclic groups consisting ofcarbon and nitrogen atoms, such as pyrrole, pyridine, piperidine, etc.,can be mentioned as the common species.

The term `3- to 7-membered homocyclic ring` means a 3- to 7-memberedhomocyclic ring consisting exclusively of carbon atoms, for instance.Thus, for example, C₃₋₇ cycloalkanes such as cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, etc., C₃₋₇ cycloalkenes such ascyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc.and benzene can be mentioned as the common species.

The divalent group derived from said "3- to 7-membered homocyclic ring"is a group resulting from either elimination of two hydrogen atoms froma single carbon atom in the 3- to 7-membered homocyclic ring orelimination of one hydrogen atom from each of two different carbonatoms. To be specific, the following groups can be included by way ofexample. ##STR14## Particularly, the following groups may be used as thecommon species. ##STR15## More preferable examples in above groupsinclude the following groups: ##STR16##

The term `3- to 7-membered heterocyclic ring` means a 3- to 7-memberedheterocyclic ring which may contain 1 to 4 hetero-atoms selected fromamong nitrogen, oxygen, sulfur and other atoms in adidtion to carbonatoms, for instance. Thus, oxetane, tetrahydrofuran, tetrahydropyran,pyrrole, azetidine, pyrrolidine, piperidine, piperazine,tetrahydrothiophene, homopiperidine, morpholine, etc. can be employed.

The divalent group derived from said "3- to 7-membered heterocyclicring" is a group resulting from either elimination of two hydrogen atomsfrom a single carbon atom in the 3- to 7-membered heterocyclic ring orelimination of one hydrogen atom from each of two different atoms. Thus,for example, the following groups can be included. ##STR17##

The term "nitrogen-containing heterocyclic group" means a groupresulting from elimination of one hydrogen atom from a nitrogen atom ina ring such as a 3- to 13-membered nitrogen-containing heterocyclic ringwhich contains one nitrogen atom in addition to carbon atoms and whichmay also contain one to four hetero atoms, for example, selected fromnitrogen, oxygen, sulfur and other atoms. Specifically, the following 3-to 9-membered nitrogen-containing heterocyclic groups can be generallyused. ##STR18##

Substituent group(s) by which said `3- to 7-membered homocyclic ring`,`3- to 7-membered heterocyclic ring` and `nitrogen-containingheterocyclic group` may optionally be substituted, may range from 1 to 5in number and are selected from among an optionally substituted loweralkyl, an optionally substituted amino, hydroxy, carboxyl, nitro, loweralkoxy (e.g. C₁₋₆ alkoxy groups such as methoxy, ethoxy, propoxy, etc.),halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. In thisconnection, substituent group(s) by which the lower alkyl (e.g. C₁₋₆alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just abovemay be substituted, may range from 1 to 4 in number and are selectedfrom among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- ordi-C₁₋₆ alkylamino groups such as methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), lower alkoxy (e.g. C₁₋₆ alkoxygroups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), loweralkylcarbonyloxy (e.g. C₁₋₆ alkylcarbonyloxy groups such as acetoxy,ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine andiodine) and so on. Substituent groups by which the amino group mentionedabove may be substituted, may range from 1 to 2 in number and areselected from among C₁₋₆ alkyl (e.g. methyl, ethyl, propyl, etc.), acyl(e.g. C₁₋₆ acyl groups such as formyl, acetyl, propionyl, butyryl,etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino,piperidino, piperazino, etc.) and so on.

In the formulas presented hereinabove, R¹ means a hydrogen atom, anoptionally substituted lower alkyl group or a halogen atom. Preferably,R¹ may for example be a hydrogen atom or a C₁₋₃ alkyl group (e.g.methyl, ethyl, n-propyl, etc.) and is more preferably a hydrogen atom.

R² and R³ each means a hydrogen atom or an optionally substituted loweralkyl group, or R² and R³ may, taken together with the adjacent --C═C--group, form a 5- to 7- membered ring. R² is preferably a hydrogen atomor a C₁₋₃ alkyl group (e.g. methyl, ethyl, n-propyl, etc.). R² is morepreferably a hydrogen atom. R³ is preferably a hydrogen atom or a C₁₋₃alkyl group (e.g. methyl, ethyl, n-propyl, etc). R³ is more preferably aC₁₋₃ alkyl group (e.g. methyl, ethyl, n-propyl, etc.). Also preferred isthe case in which R² and R³ form a 5- to 7-membered homocyclic ring incombination with the adjacent --C═C-- group. Particularly preferred isthe case of cyclohexene, benzene or the like.

X represents an oxygen atom or S(O)_(p) (p means a whole number of 0 to2). X is preferably an oxygen atom or S and more preferably an oxygenatom.

Y means a group of the formula: ##STR19## (wherein R⁴ and R⁵ each meansa hydrogen atom or a lower alkyl group which may be substituted) or adivalent group derived from a 3- to 7-membered homocyclic orheterocyclic ring which may be substituted.

Y is preferably a group of the formula: ##STR20## wherein R^(4') andR^(5') each is a hydrogen atom or an optionally substituted C₁₋₃ alkylgroup. The `C₁₋₃ alkyl` of the `optionally substituted C₁₋₃ alkylgroup`, as represented by R^(4') and R^(5'), may for example be methyl,ethyl, n-propyl or i-propyl, and the substituent groups by which suchC₁₋₃ alkyl may be substituted includes the same substituent group(s) asthose mentioned for `lower alkyl`. Particularly preferred are cases inwhich R^(4') and R^(5') each means a hydrogen atom or a C₁₋₃ alkyl group(e.g. methyl, ethyl, n-propyl, etc.). R^(4') and R^(5') each is morepreferably a C₁₋₃ alkyl group (e.g. methyl, ethyl, n-propyl, etc.)

Also preferred are cases in which Y is a divalent group derived from a3- to 7-membered homocyclic ring or heterocyclic ring which may besubstituted.

Y is preferably a group of the formula: ##STR21##

Thus, for example, the following groups can be frequently used as thecommon species of Y. ##STR22##

More preferably examples of Y include the follow: ##STR23##

R⁶ and R⁷ each is a hydrogen atom, an optionally substituted lower alkylgroup, an optionally substituted cycloalkyl group or an optionallysubstituted aryl group, and R⁶ and R⁷ may, taken together with theadjacent nitrogen atom, form a nitrogen-containing heterocyclic groupwhich may be substituted.

R⁶ and R⁷ each is preferably a hydrogen atom, a C₁₋₃ alkyl group (e.g.methyl, ethyl, n-propyl, etc.) or the like, and particularly a hydrogenatom is preferred.

m stands for a whole number of 0 to 4. It is preferably a whole numberof 1 to 4, more preferably a whole number of 1 to 3 and mostpreferably 1. n stands for a whole number of 0 to 4. It is preferably awhole number of 1 to 4 and more preferably 1. The most useful is thecase in which both m and n represent 1.

The salt of compound [I] of the present invention is preferably aphysiologically acceptable acid addition salt. Such salts include saltwith inorganic acids (e.g., hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid) and salts with organic acids (e.g.,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid). Provided thatcompound [I] of the present invention has an acidic group, such as--COOH, it may form a salt with an inorganic base (e.g., an alkali metalor alkaline earth metal such as sodium, potassium, calcium or magnesium;or ammonia) or an organic base (e.g., a tri-C₁₋₃ alkylamine such astriethylamine).

A method of producing the compound [I] or a salt thereof of the presentinvention is described below. Method A) The compound [I] or a saltthereof of the invention can be synthesized by reacting a compound ofthe general formula: ##STR24## wherein Z¹, R¹, R² and R³ are as definedhereinbefore or a salt thereof with a compound of the general formula:##STR25## wherein Z², X, Y, R⁶, R⁷, m and n are as defined hereinbeforeor a salt thereof.

The reactive group Z¹ may for example be halogen (e.g. chlorine,bromine, iodine, etc.), C₆₋₁₀ arylsulfonyloxy (e.g. benzenesulfonyloxy,p-tolylsulfonyloxy, etc.) or C₁₋₄ alkylsulfonyloxy (e.g.methanesulfonyloxy, etc.).

The group which leaves on reacting with Z¹, as represented by Z², mayfor example be a hydrogen atom or an alkali metal, e.g. sodium,potassium, etc., when X is an oxygen atom or a sulfur atom. When X is--SO-- or --SO₂, an alkali metal such as sodium, potassium, etc. isemployed.

In this reaction, the compound [III] or a salt thereof is used in aproportion of generally 1 to 5 moles and preferably 1 to 2 moles permole of the compound [II] or a salt thereof.

Generally, this condensation reaction is preferably conducted in thepresence of a base, which includes alkali metal hydrides such as sodiumhydride, potassium hydride, etc., alkali metal alkoxides such as sodiummethoxide, sodium ethoxide, etc., alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide, etc., and carbonates such as sodiumcarbonate, potassium carbonate, etc., to name but a few.

This reaction may be conducted in an inert solvent, e.g. alcohols suchas methanol, ethanol, etc., ethers such as dioxane, tetrahydrofuran,etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc.,nitriles such as acetonitrile, etc., amides such as dimethylformamide,dimethylacetamide, etc., and sulfoxides such as dimethyl sulfoxide.

The reaction temperature is generally 10° to 200° C. and preferably 50°to 100° C. The reaction time is generally 30 minutes to 24 hours andpreferably 1 to 6 hours.

Method B) The compound [I] or a salt thereof of the present inventioncan also be produced by reacting a compound of the general formula:##STR26## wherein Z², R¹, R², R³ and X are as defined hereinbefore or asalt thereof with a compound of the general formula: ##STR27## whereinZ¹, Y, R⁶, R⁷, m and n are as defined hereinbefore or a salt thereof.

In this reaction, the compound [V] or a salt thereof is used in aproportion of generally 1 to 5 moles and preferably 1 to 2 moles permole of compound [IV] or a salt thereof.

Generally, this condensation reaction is preferably conducted in thepresence of a base which includes alkali metal hydrides such as sodiumhydride, potassium hydride, etc., alkali metal alkoxides such as sodiummethoxide, sodium ethoxide, etc., alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide, etc., and carbonates such as sodiumcarbonate, potassium carbonate, etc., to name but a few.

This reaction may be conducted in an inert solvent, e.g. alcohols suchas methanol, ethanol, etc., ethers such as dioxane, tetrahydrofuran,etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc.,nitriles such as acetonitrile, etc., amides such as dimethylformamide,dimethylacetamide, etc. and sulfoxides such as dimethyl sulfoxide.

The reaction temperature is generally 10° to 200° C. and preferably 50°to 150° C. The reaction time is generally 30 minutes to 24 hours andpreferably 1 to 10 hours.

Method C) Furthermore, the compound [I] or a salt thereof can besynthesized by reacting a compound of the general formula: ##STR28##wherein W, R¹, R², R³, X, Y, m and n are as defined hereinbefore or asalt thereof with a compound of the general formula: ##STR29## whereinR⁶ and R⁷ are as defined hereinbefore or a salt thereof.

The leaving group W may for example be halogen (e.g. chlorine, bromine,iodine, etc.), C₆₋₁₀ arylsulfonyloxy (e.g. benzenesulfonyloxy,p-tolylsulfonyloxy, etc.) or C₁₋₄ alkylsulfonyloxy (e.g.methanesulfonyloxy, etc.). Particularly preferred is a halogen atom(e.g. chlorine, bromine, iodine, etc.)

In this reaction, the compound [VII] or a salt thereof is used in aproportion of generally 1 to 5 moles and preferably 1 to 2 moles permole of the compound [VI] or a salt thereof.

This reaction may be conducted in an inert solvent, e.g. alcohols suchas methanol, ethanol, etc., ethers such as dioxane, tetrahydrofuran,etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc.,nitriles such as acetonitrile, etc., amides such as dimethylformamide,dimethylacetamide, etc. and sulfoxides such as dimethyl sulfoxide.

The reaction temperature is generally -20° to 100° C. and preferably-10° to 50° C. The reaction time is generally 30 minutes to 5 hours andpreferably 1 to 3 hours.

The compound [I] or a salt thereof thus synthesized can be converted, inthe per se known manner, to a salt if it is the free form, or to thefree form or the other salt if it is a salt. The resulting compound [I]or a salt thereof can be separated and purified from the reactionmixture by the per se known procedures such as solvent extraction, pHadjustment, redistribution, precipitation, crystallization,recrystallization, chromatography and so on. Where the compound [I] or asalt thereof is an optically active compound, it can be separated intod- and l-forms by the conventional procedure for optical resolution.

The Method of producing for the starting compounds [II], [III], [IV],[V], [VI] and [VII], as well as salts thereof, which are used in theproduction of compound [I] and its salts of the present invention aredescribed below.

As salts of these compounds, there can be used salts with inorganicacids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid,sulfuric acid, etc.) and salts with organic acids (e.g. acetic acid,formic acid, propionic acid, fumaric acid, maleic acid, succinic acid,tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid,methanesulfonic acid, benzenesulfonic acid, etc.). Furthermore, wherethese compounds have acidic groups such as --COOH, they may form saltswith inorganic bases (e.g. alkali metals or alkaline earth metals suchas sodium, potassium, calcium, magnesium, etc., ammonia, etc.), ororganic bases (e.g. tri-C₁₋₃ alkylamines such as triethylamine etc.).

The starting compound [II] or a salt thereof can be synthesized by theprocess described in J. Org. Chem. 39, 2143 (1987), for instance, or anyprocess analogous thereto.

The starting compound [III] or a salt thereof and the starting compound[V] or a salt thereof can be synthesized by the processes described inChem. Ber. 91, 2130 (1958), J. Org. Chem. 52, 2162 (1987) andEP-A-381132 for instance, or any process analogous to any of theseprocesses.

The starting compound [IV] or a salt thereof can be produced by theprocess described in EP-A-381132, for instance, or any process analogousthereto.

The starting compound [VI] or a salt thereof can be synthesized, forexample (1) by reacting a compound [II] or a salt thereof with acompound of the general formula:

    Z.sup.2 X--(CH.sub.2).sub.m --Y--(CH.sub.2).sub.n --SO.sub.2 W[VIII]

wherein X, Y, Z², W, m and n are as defined hereinbefore or (2) byreacting a compound [IV] or a salt thereof with a compound of thegeneral formula:

    Z.sup.1 --(CH.sub.2).sub.m --Y--(CH.sub.2).sub.n --SO.sub.2 W[IX]

wherein Y, Z¹, W, m and n are as defined hereinbefore.

In the above reaction (1), the compound [VIII] or a salt thereof is usedin a proportion of generally 1 to 5 moles and preferably 1 to 2 molesper mole of the compound [II] or a salt thereof. This reaction can beconducted in the same manner as the above-mentioned reaction betweencompound [II] or a salt thereof and compound [III] or a salt thereof.

In the above reaction (2), the compound [IX] or a salt thereof is usedin a proportion of generally 1 to 5 moles and preferably 1 to 2 molesper mole of the compound [IV] or a salt thereof. This reaction can beconducted in the same manner as the above-mentioned reaction betweencompound [IV] or a salt thereof and compound [V] or a salt thereof.

The starting compound [VII] or a salt thereof, the starting compound[VIII] or a salt thereof and the starting compound [IX] or a saltthereof can be respectively produced by the per se known processes orany processes analogous thereto.

The starting compounds and their salts respectively synthesized as abovecan be isolated and purified by the known procedures such as solventextraction, pH adjustment, redistribution, precipitation,crystallization, recrystallization, chromatography, etc. but thereaction mixture may be directly used as the starting material for thenext process step without prior isolation.

Referring to the reactions according to the present invention and thereactions mentioned just above for synthesis of the starting materials,where the starting compounds have amino, carboxyl and/or hydroxyl groupsas a substituent, they may have been previously protected withprotective groups which are commonly used in peptide chemistry. In suchcases, the objective compound can be obtained by removing the protectivegroups as necessary after the reactions.

As such amino-protecting groups, there may be used formyl, an optionallysubstituted C₁₋₆ alkyl-carbonyl (e.g. acetyl, ethylcarbonyl, etc.),phenylcarbonyl, C₁₋₆ alkyl-oxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, etc.), phenyloxycarbonyl C₇₋₁₀ aralkylcarbonyl (e.g.benzylcarbonyl, etc.), trityl, phthaloyl, N,N-dimethylamino methyleneand so on. The substituent groups on these protective groups may rangefrom about 1 to 3 in number and include, among others, a halogen atom(e.g. fluorine, chlorine, bromine and iodine), C₁₋₆ alkyl-carbonyl (e.g.methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro and so on.

The carboxy-protecting group includes an optionally substituted C₁₋₆alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl,etc.), phenyl, trityl, silyl and other groups. The substituents on theseprotective groups may range from about 1 to 3 in number and include,among others, a halogen atom (e.g. fluorine, chlorine, bromine andiodine), formyl, C₁₋₆ alkyl-carbonyl (e.g. acetyl, ethylcarbonyl,butylcarbonyl, etc.) and nitro.

The hydroxy-protecting group includes an optionally substituted C₁₋₆alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl,etc.), phenyl, C₇₋₁₀ aralkyl (e.g. benzyl, etc.), formyl, C₁₋₆alkylcarbonyl (e.g. acetyl, ethylcarbonyl, etc.), phenyloxycarbonyl,C₇₋₁₀ aralkyl-carbonyl (e.g. benzylcarbonyl, etc.), pyranyl, furanyl,silyl and other groups. The substituents on these protective groups mayrange from about 1 to 4 in number and are selected from among a halogenatom (e.g. fluorine, chlorine, bromine and iodine), C₁₋₆ alkyl (e.g.methyl, ethyl, n-propyl, etc.), phenyl, C₇₋₁₀ aralkyl (e.g. benzyl,etc.), nitro and so on.

For elimination of these protective groups, the per se known proceduresor any procedures analogous thereto can be utilized. Such proceduresinvolve the use of an acid or a base, reduction, UV irradiation,treatment with hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride or palladiumacetate and so on.

Compound [I] of this invention or a salt thereof possesses excellentantiallergic, antiinflammatory and anti-PAF (platelet activating factor)activities and can be used safely (acute toxicity: LD₅₀ >2g/kg) as anantiasthmatic agent in mammals (e.g., humans, mice, dogs, rats,bovines). Although compound [I] of the present invention or a saltthereof may be used as such in the form of bulk powder, it is a commonpractice to administer it in the form of a preparation along withpharmaceutical carriers. Example preparations include tablets, capsules,granules, fine granules, powders, syrups, injections and inhalations.These preparations are prepared in accordance with a conventionalmethod. Examples of carriers for oral preparations include thosecommonly used in the pharmaceutical industry, such as starch, mannitol,crystalline cellulose and carboxymethylcellulose sodium. Examples ofcarriers for injections include distilled water, physiological saline,glucose solutions and transfusions. Other additives used commonly inpharmaceutical preparations may be added as appropriate. Although thedose of these preparations varies depending on age, body weight,symptoms, route and frequency of administration and other factors, theymay be administered at 0.1 to 100 mg/kg, preferably 1 to 50 mg/kg, morepreferably 1 to 10 mg/kg, in one to two portions daily for an adult.Route of administration may be oral or parenteral.

In the following, the Examples, Reference Examples, Formulation Examplesand Experiment are merely intended to describe the present invention infurther detail and should by no means be construed as defining the metesand bounds of the invention.

Detection of the fractions containing each object compound in theexamples was carried out under TLC (thin layer chromatography)monitoring. In TLC monitoring, Merck's 60F₂₅₄ was used as the TLC plateand a UV detector for detection. Further, room temperature means 15° to20° C.

Abbreviations used in the following have the following meanings.

J: coupling constant

s: singlet

bs: broad singlet

t: triplet

m: multiplet

Hz: hertz

d: doublet

q: quartet

NMR: Nuclear Magnetic Resonance

DMSO: Dimethyl sulfoxide

CDCl₃ : deuteriochloroform

v/v: volume/volume

%: weight %

m.p.: melting point

i.v.: intravenous injection

δ(ppm): chemical shift (part per million)

EXAMPLE 1 Production of6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)[1,2,4]triazolo[1,5-b]pyridazine

In 15 ml of dimethylformamide was suspended 0.42 g of 60% sodium hydridein oil, followed by addition of 0.878 g of3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirredunder reduced pressure at room temperature for 30 minutes. Then, 0.773 gof 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixturewas further stirred at room temperature for 1 hour. Following additionof 40 ml of iced water, the reaction mixture was adjusted to pH 6 with1N-hydrochloric acid and the resulting crystals were collected byfiltration and washed with 20 ml of water and 20 ml of ethyl ether. Thewashed crystals were recrystallized from hot ethanol to provide 1.16 gof the title compound. m.p. 181°-184° C.

Elemental analysis for C₁₀ H₁₅ N₅ O₃ S Calcd. (%); C, 42.10; H, 5.30; N,24.55 Found (%): C, 41.87; H, 5.28; N, 24.59

EXAMPLE 2 Production of6-(2,2-diethyl-3-sulfamoyl-1propoxy)[1,2,4]triazolo[1,5-b]pyridazine

In 20 ml of dimethylformamide was suspended 0.64 g of 60% sodium hydridein oil, followed by addition of 1.56 g of3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirredunder reduced pressure at room temperatue for 30 minutes. Then, 1.24 gof 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixturewas further stirred at room temperature for 1.5 hours. Followingaddition of 100 ml of iced water, the reaction mixture was adjusted topH 6 with 1N-hydrochloric acid and the resulting crystals were collectedby filtration and washed with 20 ml of water and 20 ml of ethyl ether.The washed crystals were recrystallized from hot ethanol to provide 1.57g of the title compound. m.p. 194°-197° C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S.0.5EtOH Calcd. (%): C, 46.41; H,6.59; N, 20.82 Found (%): C, 46.33; H, 6.68; N, 20.99

EXAMPLE 3 Production of6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

In 5 ml of tetrahydrofuran was dissolved 0.44 g of3-hydroxy-2,2-dimethyl-1-propanesulfonamide, followed by addition of 0.5ml of N,N-dimethylformamide dimethyl acetal. The mixture was allowed tostand at room temperature for 10 hours, after which it was concentratedunder reduced pressure. The residue was dissolved in 4 ml ofdimethylformamide, and following addition of 0.2 g of 60% sodium hydridein oil, the solution was stirred under reduced pressure at roomtemperature for 30 minutes. Then, 0.37 g of6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added and themixture was stirred at room temperature for 1 hour. Following additionof 50 ml of ice-water and 30 ml of 1N-hydrochloric acid, the reactionmixture was refluxed for 1 hour and adjusted to pH 6 with sodiumbicarbonate. The resulting crystals were collected by filtration andrecrystallized from aqueous methanol to provide 0.12 g of the titlecompound. m.p. 216°-218° C.

Elemental analysis for C₁₁ H₁₇ N₅ O₃ S Calcd. (%): C, 44.14; H, 5.72; N,23.39 Found (%): C, 44.13; H, 5.74; N, 23.19

EXAMPLE 4 Production of7,8-dimethyl-6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)[1,2,4]triazolo[1,5-b]pyridazine

In 30 ml of dimethylformamide was suspended 1.38 g of 60% sodium hydridein oil, followed by addition of 2.51 g of3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirredunder reduced pressure at room temperature for 1 hour. To this was added2.56 g of 6-chloro-7,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine and themixture was stirred at room temperature for 3 hours. Following additionof 100 ml of iced water, the reaction mixture was adjusted to pH 6 with5N-hydrochloric acid and extracted with 3 portions of ethylacetate-tetrahydrofuran (2:1). The extract was washed with 20 ml ofsaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate. The solvent was then distilled off under reducedpressure and the residue was subjected to silica gel columnchromatography, elution being carried out with dichloromethane-methanol(30:1). The fractions containing the desired product were pooled andconcentrated to provide 0.63 g of the title compound. m.p. 175°-177° C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S Calcd. (%): C, 45.99; H, 6.11; N,22.35 Found (%): C, 46.27; H, 6.14; N, 22.16

EXAMPLE 5 Production of6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

In 20 ml of dimethylformamide was suspended 0.672 g of 60% sodiumhydride in oil, followed by addition of 1.72 g of3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirredunder reduced pressure at room temperature for 1 hour. To this was added1.35 g of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and themixture was stirred under a nitrogen atmosphere at room temperature for2 hours. Following addition of 70 ml of iced water, the reaction mixturewas adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washedwith saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate. The solvent was then distilled off underreduced pressure and the residue was subjected to silica gel columnchromatography, elution being carried out with dichloromethane-ethylacetate-methanol (10:10:1). The fractions containing the object productwere pooled and concentrated, and 50 ml of 5N-hydrochloric acid wasadded to the residue. The mixture was refluxed for 30 minutes. Aftercooling, the mixture was concentrated under reduced pressure and theresidue was diluted with water and aqueous solution of sodium hydrogencarbonate and extracted with 3 portions of ethyl acetate-tetrahydrofuran(1:1). The extract was washed with saturated aqueous solution of sodiumchloride once, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was recrystallized from hot ethanolto provide 0.79 g of the title compound. m.p. 189°-192° C.

Elemental analysis for C₁₃ H₂₁ N₅ O₃ S.0.5EtOH Calcd. (%): C, 47.98; H,6.90; N, 19.90 Found (%): C, 47.44; H, 6.84; N, 19.93

EXAMPLE 6 Production of6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

To a solution of 1.38 g of3-(N,N-dimethylamino-methylene)aminosulfonyl-2,2-diethyl-1-propanol in30 ml of tetrahydrofuran was added 0.23 g of 60% sodium hydride in oiland the mixture was stirred at room temperature for 1 hour. To thisreaction mixture was added 0.74 g of6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture wasrefluxed with stirring for 1 hour. After cooling, the reaction mixturewas adjusted to pH 6 with 1N-hydrochloric acid and extracted with ethylacetate-tetrahydrofuran (1:1). The extract was washed with water anddried and the solvent was distilled off. To the residue was added 14 mlof 6N-hydrochloric acid and the mixture was stirred at 110° C. for 30minutes. After cooling, 100 ml of water was added to the reactionmixture and the resulting crystals were recovered by filtration andrecrystallized from methanol to provide 1.16 g of the title compound.m.p. 208°-209° C.

Elemental analysis for C₁₃ H₂₁ N₅ O₃ S Calcd. (%): C, 47.69; H, 6.46; N,21.39 Found (%): C, 47.46; H, 6.44; N, 21.59

Recrystallization of this product from hot ethanol gave the crystalscontaining ethanol as obtained in Example 5.

EXAMPLE 7 Production of6-(2,2-dimethyl-4-sulfamoyl-1-butoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 4-hydroxy-3,3-dimethyl-1-butanesulfonamide and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction wasconducted as in Example 5 to produce the title compound. m.p. 214°-215°C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S Calcd. (%): C, 45.99; H, 6.11; N,22.35 Found (%): C, 45.80; H, 5.91; N, 22.56

NMR (d₆ -DMSO) δ: 1.06 (6H, s), 1.80-1.95 (2H, m), 2.33 (3H, s),2.97-3.09 (2H, m), 4.09 (2H, s), 6.75 (2H, s), 8.16 (1H, s), 8.38 (1H,s)

EXAMPLE 8 Production of6-(2,2-dimethyl-5-sulfamoyl-1-pentyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 5-hydroxy-4,4-dimethyl-1-pentanesulfonamide and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction wasconducted as in Example 5 to produce the title compound. m.p. 171°-172°C.

Elemental analysis for C₁₃ H₂₁ N₅ O₃ S Calcd. (%): C, 47.69; H, 6.46; N,21.39 Found (%): C, 47.45; H, 6.39; N, 21.18

NMR (CDCl₃) δ: 1.05 (6H, s), 1.45-1.59 (2H, m), 1.66-1.82 (2H, m), 2.33(3H, s), 2.96 (2H, t, J=7.8 Hz), 4.08 (2H, s), 6.72 (2H, bs), 8.15 (1H,s) , 8.37 (1H, s)

EXAMPLE 9 Production of6-(2,2-dimethyl-6-sulfamoyl-1-hexyloxy)-7-methyl[1,24]triazolo[1,5-b]pyridazine

Using 6-hydroxy-5,5-dimethyl-1-hexanesulfonamide and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction wasconducted as in Example 5 to produce the title compound. m.p. 161°-163°C.

Elemental analysis for C₁₄ H₂₃ N₅ O₃ S Calcd. (%): C, 49.25; H, 6.79; N,20.51 Found (%): C, 48.99; H, 6.68; N, 20.74

NMR (d₆ -DMSO) δ: 1.05 (6H, s), 1.38-1.60 (4H, m), 1.67-1.98 (4H, m),2.37 (3H, s), 3.15 (2H, t, J=7.8 Hz), 4.14 (2H, s), 4.77 (2H, bs), 7.78(1H, s), 8.25 (1H, s)

EXAMPLE 10 Production of6-(2,2-diethyl-6-sulfamoyl-1-hexyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 6-hydroxy-5,5-diethyl-1-hexanesulfonamide and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction wasconducted as in Example 5 to produce the title compound. m.p. 132°-133°C.

Elemental analysis for C₁₆ H₂₇ N₅ O₃ S Calcd. (%): C, 52.01; H, 7.37; N,18.95 Found (%): C, 51.89; H, 7.10; N, 19.08

NMR (CDCl₃) δ: 0.85 (6H, t, J=7.4 Hz), 1.35-1.55 (8H, m), 1.78-1.98 (2H,m), 3.13 (2H, t, J=8.0 Hz), 4.18 (2H, s), 4.76 (2H, bs), 7.77 (1H, s),8.25 (1H, s)

EXAMPLE 11 Production of6-(2,2-diethyl-5-sulfamoyl-1-pentyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 5-hydroxy-4,4-diethyl-1-pentanesulfonamide and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction wasconducted as in Example 5 to produce the title compound. m.p. 157°-158°C.

NMR (CDCl₃) δ: 0.86 (6H, t, J=7.4 Hz), 1.46 (4H, q, J=7.4Hz), 1.48 (2H,t, J=7.6 Hz), 1.79-1.98 (2H, m), 2.36 (3H, s), 3.07 (2H, t, J=7.6 Hz),4.21 (2H, s), 5.54 (2H, bs), 7.76 (1H, s), 8.24 (1H, s)

EXAMPLE 12 Production of6-(2,2-diethyl-4-sulfamoyl-1-butoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-butanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.148°-149° C.

Elemental analysis: for C₁₄ H₂₃ N₅ O₃ S Calcd. (%): C, 49.25; H, 6.79;N, 20.51 Found (%): C, 48.99; H, 6.68; N, 20.24

NMR (d₆ -DMSO) δ: 0.84 (6H, t, J=7.0 Hz), 1.42 (4H, q, J=7.0 Hz),1.76-1.91 (2H, m), 2.31 (3H, s), 2.89-3.03 (2H, m), 4.11 (2H, s), 6.77(2H, bs), 8.15 (1H, s), 8.39 (1H, s)

EXAMPLE 13 Production of6-(2,2-pentamethylene-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-pentamethylene-1-propanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.268°-270° C.

Elemental analysis for C₁₄ H₂₁ N₅ O₃ S Calcd. (%): C, 49.54; H, 6.24; N,20.63 Found (%): C, 49.19; H, 6.22; N, 20.40

NMR (d₆ -DMSO) δ: 1.28-1.89 (10H, m), 2.34 (3H, s), 3.34 (2H, s), 4.43(2H, s), 6.94 (2H, bs), 8.16 (1H, s), 8.39 (1H, s)

EXAMPLE 14 Production of6-(3,3-dimethyl-5-sulfamoyl-1-pentyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethyl-1-pentanol and6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction asin Example 6 was conducted to produce the title compound. m.p. 143°-144°C.

Elemental analysis: for C₁₃ H₂₁ N₅ O₃ S Calcd. (%): C, 47.69; H, 6.46;N, 21.39 Found (%): C, 47.50; H, 6.53; N, 21.13

NMR (d₆ -DMSO) δ: 1.00 (6H, s), 1.66-1.89 (4H, m), 2.30 (3H, s),2.94-3.10 (2H, m), 4.43 (2H, t, J=6.8. Hz), 6.77 (2H, bs), 8.16 (1H, s),8.39 (1H, s)

EXAMPLE 15 Production of6-(4,4-dimethyl-6-sulfamoyl-1-hexyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 6-(N,N-dimethylaminomethylene)aminosulfonyl-4,4-dimethyl-1-hexanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.154°-155° C.

Elemental analysis for C₁₄ H₂₃ N₅ O₃ S Calcd. (%): C, 49.25; H, 6.79; N,20.51 Found (%): C, 48.98; H, 7.02; N, 20.86

NMR (d₆ -DMSO) δ: 0.91 (6H, s), 1.29-1.46 (2H, m), 1.57-1.88 (4H, m),2.30 (3H, s), 2.85-3.04 (2H, m), 4.35 (2H, t, J=6.3 Hz), 6.75 (2H, bs),8.15 (1H, s), 8.37 (1H, s)

EXAMPLE 16 Production of6-(2,2-pentamethylene-4-sulfamoyl-1-butoxy)-7-methyl[1,2,4]triazolo[1,5-6]pyridazine

Using4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-pentamethylene-1-butanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, substantially thesame reaction as in Example 6 was conducted to produce the titlecompound. m.p. 208°-209° C.

Elemental analysis for C₁₅ H₂₃ N₅ O₃ S Calcd. (%): C, 50.97; H, 6.56; N,19.81 Found (%): C, 51.24; H, 6.55; N, 19.58

NMR (d₆ -DMSO) δ: 1.32-1.65 (10H, m), 1.86-2.03 (2H, m), 2.32 (3H, s),2.90-3.04 (2H, m), 4.16 (2H, s), 6.75 (2H, bs), 8.14 (1H, s), 8.38 (1H,s)

EXAMPLE 17 Production of6-(2-isopropyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-isopropyl-1-propanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.196°-197° C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S Calcd. (%): C, 45.99; H, 6.11; N,22.35 Found (%): C, 45.85; H, 6.18; N, 22.00

NMR (d₆ -DMSO) δ: 0.97 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),1.98-2.19 (1H, m), 2.25-2.43 (1H, m), 2.31 (3H, s), 3.03-3.27 (2H, m),4.40-4.59 (2H, m), 6.93 (2H, bs), 8.16 (1H, s), 8.39 (1H, s)

EXAMPLE 18 Production of6-(2-ethyl-2-methyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine

Using3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanoland 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.189°-190° C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S Calcd. (%): C, 45.99; H, 6.11; N,22.35 Found (%): C, 46.17; H, 6.18; N, 22.19

NMR (d₆ -DMSO) δ: 0.90 (3H, t, J=7.4 Hz), 1.20 (3H, s), 1.66 (2H, q,J=7.4 Hz), 2.34 (3H, s), 3.22 (2H, d, J=3.6 Hz), 4.31 (2H, s), 6.93 (2H,bs), 8.16 (1H, s), 8.39 (1H, s)

EXAMPLE 19 Production of6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine

Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanoland 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the samereaction as in Example 6 was conducted to produce the title compound.m.p. 221°-222° C.

Elemental analysis: for C₁₄ H₂₃ N₅ O₃ S Calcd. (%): C, 49.25; H, 6.79;N, 20.51 Found (%): C, 49.36; H, 6.56; N, 20.71

NMR (d₆ -DMSO) δ: 0.88 (6H, t, J=7.2 Hz), 1.62 (4H, q, J=7.2 Hz), 2.31(3H, s), 2.49 (3H, s), 3.21 (2H, s), 4.31 (2H, s), 6.93 (2H, bs), 8.02(1H, s)

EXAMPLE 20 Production of2,7-dimethyl-6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)[1,2,4]triazolo[1,5-b]pyridazine

Using3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-dimethyl-1-propanol and6-chloro-2,7-dimethyl[1,2,4]trizolo[1,5-b]pyridazine, the same reactionas in Example 6 was conducted to produce the title compound. m.p.217°-218° C.

Elemental analysis for C₁₂ H₁₉ N₅ O₃ S Calcd. (%): C, 45.99; H, 6.11; N,22.35 Found (%) : C, 46.02; H, 5.99; N, 22.36

EXAMPLE 21 Production of6-(2-ethyl-2-methyl-3-sulfamoyl-1-propoxy)-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine

Using3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanoland 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the samereaction as in Example 6 was conducted to produce the title compound.m.p. 194°-195° C.

Elemental analysis for C₁₃ H₂₁ N₅ O₃ S Calcd. (%): C, 47.69; H, 6.46; N,21.39 Found (%): C, 47.63; H, 6.32; N, 21.57

EXAMPLE 22 Production of6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-2,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine

Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanoland 6-chloro-2,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the samereaction as in Example 6 was conducted to produce the title compound.m.p. 159°-160° C.

Elemental analysis for C₁₄ H₂₃ N₅ O₃ S Calcd. (%): C, 49.25; H, 6.79; N,20.51 Found (%): C, 49.04; N, 6.65; N, 20.36

EXAMPLE 23 Production of2,7-dimethyl-6-(2,2-pentamethylene-4-sulfamoyl-1-butoxy)[1,2,4]triazolo[1,5-b]pyridazine

Using4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-pentamethylene-1-butanoland 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the samereaction as in Example 6 was conducted to produce the title compound.m.p. 204°-205° C.

Elemental analysis for C₁₆ H₂₅ N₅ O₃ S Calcd. (%) : C, 52.30; H, 6.86;N, 19.06 Found (%) : C, 52.45; H, 6.90; N, 18.78

EXAMPLE 24 Production of6-(3-sulfamoyl-1-propoxy)[1,2,4]triazolo[1,5-b]pyridazine

In 12 ml of dimethylformamide was suspended 0.48 g of 60% sodium hydridein oil followed by addition of 0.835 g of 3-hydroxy-1-propanesulfonamideand the mixture was stirred under reduced pressure at room temperaturefor 30 minutes. Then, 0.928 g of6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture wasfurther stirred at room temperature for 18 hours. Following addition of40 ml of ice water, the reaction mixture was adjusted to pH6 with1N-hydrochloric acid then saturated with sodium chloride. The aqueouslayer was extracted with tetrahydrofuran and the extract was dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was crystallized from ethyl ether. The washedcrystals were recrystallized from hot methanol to provide 0.811 g oftitle compound. m.p. 145°-147° C.

Elemental analysis for C₈ H₁₁ N₅ O₃ S Calcd. (%): C, 37.35; H, 4.31; N,27.22 Found (%): C, 37.48; H, 4.33; N, 26.95

EXAMPLE 25 Production of6-[3-(N,N-dimethylsulfamoyl)-1-propoxy][1,2,4]triazolo[1,5-b]pyridazine

In 10 ml of dimethylformamide was suspended 0.252 g of 60% sodiumhydride in oil followed by addition of 1.0 g ofN,N-dimethyl-3-hydroxypropane-1-sulfonamide and the mixture was stirredunder reduced pressure at room temperature for 30 minutes. Then, 0.928 gof 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixturewas further stirred at room temperature for 1.5 hours. Followingaddition of 30 ml of ice water, the reaction mixture was adjusted to pH4.0 with 1N-hydrochloric acid and the resulting crystals were collectedby filtration and recrystallized from hot methanol to provide 1.255 g ofthe title compound. m.p. 151°-153° C.

Elemental analysis for C₁₀ H₁₅ N₅ O₃ S Calcd. (%) : C, 42.10; H, 5.30;N, 24.55 Found (%): C, 42.17; H, 5.21; N, 24.69

EXAMPLE 26 Production of6-[3-(1-methyl-4-piperazinylsulfonyl)-1-propoxy][1,2,4]triazolo[1,5-b]pyridazine

In 10 ml of dimethylformamide was suspended 0.21 g of 60% sodium hydridein oil followed by addition of 1.12 g of3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture wasstirred under reduced pressure at room temperature for 75 minutes. Then,0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and themixture was further stirred at room temperature for 1.5 hours. Followingaddition of 40 ml of ice water, the reaction mixture was saturated withsodium chloride. The aqueous layer was extrated with tetrahydrofuran andthe extrat was dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure and the residue was subjected tosilica gel column chromatography, elution being carried out withdichloromethane-methanol (10:1). The fractions containing the desiredproduct were pooled and concentrated to provide 1.032 g of the titlecompound. m.p. 140°-141° C.

Elemental analysis for C₁₃ H₂₀ N₆ O₃ S Calcd. (%): C, 45.87; H, 5.92; N,24.69 Found (%): C, 45.67; H, 5.94; N. 24.90

EXAMPLE 27 Production of6-(3-sulfamoyl-1-propylthio)[1,2,4]triazolo[1,5-b]pyridazine

In 20 ml of methanol was dissolved 1.94 ml of methyl3-mercaptopropionate followed by addition of 7.5 ml of 2N sodiummethoxide in methanol and 0.773 g of6-chloro[1,2,4]triazolo[1,5-b]pyridazine. The solution was refluxed for30 minutes. After cooling, the mixture was concentrated under reducedpressure. To the residue was added ethyl acetate and the resultingcrystals were collected by filtration. In 20 ml of tetrahydrofuran weresuspended the crystals followed by addition of 0.997 g of3-iodopropane-1-sulfonamide and the mixture was refluxed for 2.5 hours.After cooling, the solvent was distilled off under reduced pressure andthe residue was treated with 20 ml of ice water and adjusted to pH 4with 1N-hydrochloric acid. The resulting crystals were collected byfiltration and recrystallized from methanol to provide 0.856 g of thetitle compound. m.p. 130°-131° C.

Elemental analysis for C₈ H₁₁ N₅ O₂ S₂ Calcd. (%): C, 35.15; N, 4.06; N,25.62 Found (%): C, 35.17; N. 4.06; N, 25.55

REFERENCE EXAMPLE 1 Production of ethyl 4-chloro-2,2-dimethylbutyrate

To a solution of 22.2 ml of diisopropylamine in 150 ml oftetrahydrofuran was added 93.6 ml of 1.6M n-butyllithium-hexane withstirring at -5° to 0° C. and the mixture was stirred for 30 minutes. Thereaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyratewas added dropwise. The mixture was then further stirred for 45 minutes,after which a solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml oftetrahydrofuran was added dropwise. The reaction mixture was stirred at-78° C. for 1 hour and, then, at room temperature for 2 hours. After anexcess amount of an aqueous solution of ammonium chloride was added, themixture was extracted with ethyl acetate. The extract was washed withwater and dried (MgSO₄) and the solvent was distilled off. Finally, theresidue was distilled under reduced pressure to provide 24.7 g of thetitle compound as colorless oil. b.p. 54°-56° C./0.25 mmHg

NMR (CDCl₃) δ: 1.22 (6H, s), 1.26 (3H, t, J=7.0Hz), 2.06 (2H, t, J=8.1Hz), 3.51 (2H, t, J=8.1 Hz), 4.14 (2H, q, J=7.0 Hz)

REFERENCE EXAMPLE 2 Production of ethyl 2,2-dimethyl-4-thiocyanobutyrate

In 100 ml of dimethylformamide were dissolved 22.1 g of ethyl4-chloro-2,2-dimethylbutyrate and 14.5 g of potassium thiocyanate andthe solution was stirred at 100° C. for 7 hours. The reaction mixturewas poured in 500 ml of water and extracted with ethyl ether. Theextract was washed with water and dried (MgSO₄) and the solvent wasdistilled off. The residue was subjected to vacuum distillation toprovide 16.4 g of the title compound as colorless oil. b.p. 109°-111°C./0.3 mmHg

NMR (CDCl₃) δ: 1.24 (6H, s), 1.27 (3H, t, J=7.2 Hz), 2.00-2.12 (2H, m),2.86-2.97 (2H, m), 2.86-2.97 (2H, m), 4.15 (2H, q, J=7.2 Hz).

REFERENCE EXAMPLE 3 Production of ethyl4-aminosulfonyl-2,2-dimethylbutyrate

In a mixture of 200 ml of acetic acid and 200 ml of water was dissolved42.5 g of ethyl 2,2-dimethyl-4-thiocyanobutyrate and while the solutionwas vigorously stirred, chlorine gas was bubbled through the solution at10° to 15° C. for 3 hours. The reaction mixture was then stirred at roomtemperature for 30 minutes, after which it was diluted with 500 ml ofwater and extracted with dichloromethane. The extract was washed withwater and dried (MgSO₄) and the solvent was distilled off. The residuewas dissolved in dichloromethane (250 ml) and ammonia gas was bubbledthrough the solution at 10° to 15° C. for 2 hours. The insolubles werefiltered off and the filtrate was washed with water and dried (MgSO₄).The solvent was then distilled off. The residue was subjected to silicagel column chromatography and elution was carried out with hexane-ethylacetate (3:1) to provide 40.7 g of the title compound as colorless oil.

NMR (CDCl₃) δ: 1.23 (6H, s), 1.26 (3H, t, J=7.2 Hz), 2.00-2.13 (2H, m),3.06-3.19 (2H, m), 4.14 (2H, q, J=7.2 Hz), 4.86 (2H, br)

REFERENCE EXAMPLE 4 Production of4-hydroxy-3,3-dimethyl-1-butanesulfonamide

While a suspension of 0.35 g of lithium aluminum hydride in 30 ml oftetrahydrofuran was stirred with ice-cooling, a solution of 1.5 g ofethyl 4-aminosulfonyl-2,2-dimethylbutyrate in 8 ml of tetrahydrofuranwas added dropwise. After completion of dropwise addition, the mixturewas stirred at 0° C. for 30 minutes and, then, at room temperature for30 minutes. To this reaction mixture was added aqueous tetrahydrofuranfor decomposition of excess lithium aluminum hydride and the mixture wasneutralized with 2N-hydrochloric acid and extracted with ethyl acetate.The extract was washed with water and dried (MgSO₄) and the solvent wasdistilled off. The residue was subjected to silica gel columnchromatography and elution was carried out with hexane-ethyl acetate(1:1) to provide 0.94 g of the title compound. m.p.: 75°-76° C.

Elemental analysis: for C₆ H₁₅ NO₃ S Calcd. (%): C, 39.75; H, 8.34; N,7.73 Found (%): C, 39.80; H, 8.10; N, 7.92

REFERENCE EXAMPLE 5 Production of4-(N,N-dimethylaminomethylene)amino-sulfonyl-2,2-dimethyl-1-butanol

To a suspension of 2.3 g of 4-hydroxy-3,3-dimethyl-1-butanesulfonamidein 40 ml of toluene was added 1.59 g of N,N-dimethylformamide dimethylacetal and the mixture was stirred at 70° C. for 40 minutes. The solventwas then distilled off and the residue was recrystallized from ethylether to provide 2.86 g of the title compound.

NMR (CDCl₃) δ: 0.91 (6H, s), 1.69-1.84 (2H, m), 1.94 (1H, t, J=4.8 Hz),2.98-3.11 (2H, m), 3.05 (3H, s), 3.14 (3H, s), 3.34 (2H, d, J=4.8 Hz),8.05 (1H, s)

REFERENCE EXAMPLE 6 Production of3-(N,N-dimethylaminomethylene)amino-sulfonyl-2,2-diethyl-1-propanol

A mixture of 6.0 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide, 4.0 gof N,N-3-dimethylformamide dimethyl acetal and 60 ml of toluene wasstirred at 100° C. for 30 minutes. The solvent was then distilled off.The residue was subjected to silica gel column chromatography andelution was carried out with ethyl acetate-chloroform-methanol (20:20:1)to provide 6.4 g of the title compound as colorless oil.

NMR (CDCl₃) δ: 0.84 (6H, t, J=7.4 Hz), 1.49 (4H, q, J=7.4 Hz), 3.05 (4H,s), 3.15 (3H, s), 3.64 (2H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 7 Production of3-(N,N-dimethylaminomethylene)amino-sulfonyl-2,2-pentamethylene-1-propanol

Using 3-hydroxy-2,2-pentamethylene-1-propanesulfonamide andN,N-dimethylformamide dimethyl acetal, the same reaction as in ReferenceExample 5 was conducted to produce the title compound.

NMR (CDCl₃) δ: 1.36-1.73 (10H, m), 2.72 (1H, br), 3.05 (3H, s), 3.14(2H, s), 3.15 (3H, s), 3.72 (3H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 8 Production of4-(N,N-dimethylaminomethylene)amino-sulfonyl-1-iodo-2,2-dimethylbutane

A mixture of 5.5 g of 4-hydroxy-3,3-dimethyl-1-butanesulfonamide, 3.98 gof N,N-dimethylformamide dimethyl acetal and 50 ml of benzene wasstirred at 80° C. for 1 hour. The solvent was then distilled off and theresidue was dissolved in 50 ml of dichloromethane. While this solutionwas stirred with ice-cooling, 6.6 ml of anhydroustrifluoromethanesulfonic acid was added dropwise. After completion ofdropwise addition, the mixture was stirred for 20 minutes, at the end ofwhich time 4.7 ml of 2,6-lutidine was added and the reaction was furtherconducted at 0° C. for 20 minutes. The reaction mixture was diluted with100 ml of water and extracted with ethyl acetate. The extract was washedserially with aqueous solution of potassium hydrogen sulfate and waterand dried and the solvent was distilled off. The resulting oil wasdissolved in 100 ml of acetone and after 13.5 g of sodium iodide wasadded, the mixture was refluxed with stirring for 2 hours. Aftercooling, the reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with water and dried and thesolvent was distilled off. The residue was subjected to silica gelcolumn chromatography and elution was carried out with ethylacetate-hexane (3:1). The fractions containing the objective productwere pooled and concentrated and the residue was crystallized fromisopropyl ether to provide 8.44 g of the title compound. m.p. 81°-82° C.

Elemental analysis: for C₉ H₁₉ IN₂ O₂ S Calcd. (%): C, 31.22; H, 5.53;N, 8.09 Found (%): C, 31.67; H, 5.68; N, 8.18

NMR (CDCl₃) δ: 1.07 (6H, s), 1.78-1.91 (2H, m), 2.92-3.04 (2H, m), 3.06(3H, s), 3.12 (2H, s), 3.16 (3H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 9 Production of1-cyano-4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-dimethylbutane

A mixture of 1.85 g of4-(N,N-dimethylaminomethylene)aminosulfonyl-1-iodo-2,2-dimethylbutane,0.49 g of potassium cyanide, 0.06 g of 18-crown-6 and 30 ml of dimethylsulfoxide was stirred at 100° C. for 14 hours. After cooling, thereaction mixture was diluted with 100 ml of water and extracted withethyl acetate. The extract was washed with water and dried (MgSO₄) andthe solvent was distilled off. The residue was subjected to silica gel(70 g) column chromatography and elution was carried out with ethylacetate-hexane (9:1). The fractions containing the objective compoundwere pooled and concentrated and the residue was recrystallized fromethyl ether to provide 1.11 g of the title compound. m.p. 53°-54° C.

Elemental analysis for C₁₀ H₁₉ N₃ O₂ S Calcd. (%): C, 48.96; H, 7.81; N,17.13 Found (%): C, 48.88; H, 7.82; N, 16.77

NMR (CDCl₃) δ: 1.10 (6H, s), 1.82-1.94 (2H, m), 2.27 (2H, s), 2.96-3.07(2H, m), 3.05 (3H, s), 3.15 (3H, s), 8.04 (1H, s)

REFERENCE EXAMPLE 10 Production of methyl5-aminosulfonyl-3,3-dimethylvalerate

A mixture of 0.49 g of the cyano compound obtained in Reference Example9 and 10 ml of concentrated hydrochloric acid was stirred at 120° to130° C. for 16 hours and, then, concentrated to dryness under reducedpressure. The residue was dissolved in 12 ml of methanol and after 4drops of concentrated sulfuric acid was added, the mixture was refluxedfor 14 hours. The methanol was distilled off and the residue was dilutedwith water and extracted with ethyl acetate. The extract was washed withwater and dried (MgSO₄) and the solvent was distilled off. The residuewas subjected to silica gel (60 g) column chromatography and elution wascarried out with ethyl acetate-hexane (4:1) to provide 0.35 g of thetitle compound as oil.

NMR (CDCl₃) δ: 1.05 (6H, s), 1.84-1.98 (2H, m), 2.25 (2H, s), 3.10-3.23(2H, m), 3.68 (3H, s), 5.01 (2H, bs)

REFERENCE EXAMPLE 11 Production of5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethyl-1-pentanol

In 10 ml of tetrahydrofuran was dissolved 0.352 g of the methyl esterobtained in Reference Example 10 and while the solution was stirred withice-cooling, a suspension of 0.101 g of lithium aluminum hydride in 20ml of tetrahydrofuran was added dropwise. The mixture was furtherstirred at the same temperature for 40 minutes, after which aqueoustetrahydrofuran was added. The mixture was then neutralized with2N-hydrochloric acid and extracted with ethyl acetate. The extract waswashed with water and dried (MgSO₄) and the solvent was distilled off.The residue was dissolved in 8 ml of toluene followed by addition of0.24 g of N,N-dimethylformamide dimethyl acetal. The mixture was stirredat 80° C. for 45 minutes, after which the solvent was distilled off. Theresidue was subjected to silica gel (60 g) column chromatography andelution was carried out with chloroform-methanol (20:1) to provide 0.286g of the title compound as oil.

Elemental analysis: for C₁₀ H₂₂ N₂ O₃ S Calcd. (%): C, 47.97; H, 8.86;N, 11.19 Found (%): C, 47.71; H, 8.62; N, 11.44

NMR (CDCl₃) δ: 0.94 (6H, s), 1.52 (2H, t, J=7.2 Hz), 1.67-1.81 (3H, m),2.94-3.06 (2H, m), 3.04 (3H, s), 3.14 (3H, s), 3.70 (2H, t, J=7.2 Hz),8.03 (1H, s)

REFERENCE EXAMPLE 12 Production of5-(N,N-dimethylaminomethylene)aminosulfonyl-1-iodo-3,3-dimethylpentane

In 10 ml of dichloromethane was dissolved 0.25 g of the5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethyl-1-pentanolobtained in Reference Example 11 and while the solution was stirred withice-cooling, 0.24 ml of anhydrous trifluoromethanesulfonic acid wasadded dropwise. After completion of dropwise addition, the mixture wasstirred at the same temperature for 20 minutes. Then, 0.18 ml of2,6-lutidine was added and the mixture was further stirred for 20minutes. The reaction mixture was then diluted with water and extractedwith dichloromethane. The extract was washed serially with aqueoussolution of potassium hydrogen sulfate and water and dried (MgSO₄) andthe solvent was distilled off. The residue was dissolved in 15 ml ofacetone, followed by addition of 0.5 g of sodium iodide, and the mixturewas refluxed for 2 hours. After cooling, the reaction mixture wasdiluted with water and extracted with ethyl acetate. The extract waswashed with water and dried (MgSO₄) and the solvent was distilled off.The residue was subjected to silica gel (50 g) column chromatography andelution was carried out with ethyl acetate-hexane (4:1) to provide 0.267g of the title compound. m.p. 105°-106° C.

Elemental analysis for C₁₀ H₂₁ IN₂ O₂ S Calcd. (%): C, 33.34; H, 5.88;N, 7.78 Found (%): C, 33.57; H, 5.97; N, 8.09

REFERENCE EXAMPLE 13 Production of1-cyano-5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethylpentane

A mixture of 7.2 g of the5-(N,N-dimethylamino-methylene)aminosulfonyl-1-iodo-3,3-dimethylpentaneobtained in Reference Example 12, 1.95 g of potassium cyanide, 0.26 g of18-crown-6 and 100 ml of dimethyl sulfoxide was stirred at 90° C. for 5hours. After cooling, the reaction mixture was diluted with 300 ml ofwater and extracted with ethyl acetate. The extract was washed withwater and dried and the solvent was distilled off under reducedpressure. The residue was subjected to silica gel (100 g) columnchromatography and elution was carried out with ethyl acetate-chloroform(5:1). The fractions containing the objective product were pooled andconcentrated to provide 4.23 g of the title compound as colorless oil.

NMR (CDCl₃) δ: 0.94 (6H, s), 1.57-1.80 (4H, m), 2.32 (2H, t, J=7.6 Hz),2.91-3.04 (2H, m), 3.05 (3H, s), 3.15 (3H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 14 Production of methyl6-aminosulfonyl-4,4-dimethylhexanoate

A mixture of 3.6 g of the1-cyano-5-(N,N-dimethylamino-methylene)aminosulfonyl-3,3-dimethylpentaneobtained in Reference Example 13 and 30 ml of concentrated hydrochloricacid was stirred at 120° to 130° C. for 10 hours, at the end of whichtime it was concentrated to dryness under reduced pressure. The residuewas dissolved in 50 ml of methanol, followed by addition of 0.3 ml ofconcentrated sulfuric acid, and the mixture was refluxed for 6 hours.The methanol was then distilled off and the residue was diluted withwater and extracted with ethyl acetate. The extract was washed withwater and dried and the solvent was distilled off. The residue wassubjected to silica gel (100 g) column chromatography and elution wascarried out with ethyl acetate-hexane (2:1) to provide 2.95 g of thetitle compound as oil.

NMR (CDCl₃) δ: 0.93 (6H, s), 1.54-1.85 (4H, m), 2.30 (2H, t, J=8.0 Hz),3.10 (2H, d, J=8.0 Hz), 3.68 (3H, s), 4.89 (2H, bs)

REFERENCE EXAMPLE 15 Production of6-(N,N-dimethylaminomethylene)aminosulfonyl-4,4-dimethyl-1-hexanol

In 20 ml of tetrahydrofuran was dissolved 3.3 g of the methyl6-aminosulfonyl-4,4-dimethylhexanoate obtained in Reference Example 14and while the solution was stirred with ice-cooling, a suspension of0.79 g of lithium aluminum hydride in 100 ml of tetrahydrofuran wasadded dropwise. The mixture was stirred at the same temperature for 40minutes, after which aqueous tetrahydrofuran was added. The mixture wasthen neutralized with 2N-hydrochloric acid and extracted with ethylacetate. The extract was washed with water and dried and the solvent wasdistilled off. The residue was dissolved in 50 ml of toluene, followedby addition of 1.85 ml of N,N-dimethylformamide dimethyl acetal, and themixture was stirred at 80° C. for 1 hour. The solvent was then distilledoff. The residue was subjected to silica gel (80 g) columnchromatography and elution was carried out with chloroform-methanol(20:1) to provide 3.15 g of the title compound as oil.

NMR (CDCl₃) δ: 0.90 (6H, s), 1.20-1.33 (2H, m), 1.46-1.78 (4H, m), 1.61(1H, s), 2.98 (2H, t, J=6.4 Hz), 3.05 (3H, s), 3.14 (3H, s), 3.62 (2H,t, J=6.4 Hz), 8.04 (1H, s)

REFERENCE EXAMPLE 16 Production of ethyl 5-bromo-2,2-dimethylvalerate

To a solution of 28.7 ml of diisopropylamine in 150 ml oftetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane withstirring at -5° to 0° C. and the mixture was further stirred for 30minutes. This reaction mixture was cooled to -78° C. and 26.7 ml ofethyl isobutyrate was added dropwise. The mixture was stirred for 1hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. Thereaction mixture was stirred at -78° C. for 1 hour and then at roomtemperature for 2 hours. The mixture was then poured in aqueous solutionof ammonium chloride and extracted with ethyl acetate. The extract waswashed with water and dried. The solvent was then distilled off and theresidue was subjected to vacuum distillation to provide 40.3 g of thetitle compound as colorless oil. b.p. 76°-78° C./0.27 mmHg

NMR (CDCl₃) δ: 1.19 (6H, s), 1.25 (3H, t, J=7.2 Hz), 1.31-1.60 (4H, m),3.30-3.50 (2H, m), 4.12 (2H, q,J=7.2 Hz)

REFERENCE EXAMPLE 17 Production of ethyl 6-bromo-2,2-dimethylhexanoate

Using ethyl isobutyrate and 1,4-dibromobutane, the same reaction as inReference Example 16 was conducted to produce the title compound. b.p.62°-64° C./0.4 mmHg

NMR (CDCl₃) δ: 1.17 (6H, s), 1.25 (3H, t, J=7.2 Hz), 1.33-1.63 (4H, m),3.33-3.50 (4H, m), 4.12 (2H, q, J=7.2 Hz)

REFERENCE EXAMPLE 18 Production of ethyl 4-chloro-2,2-diethybutyrate

Using ethyl 2-ethylbutyrate and 1-bromo-2-chloroethane, the samereaction as in Reference Example 16 was conducted to produce the titlecompound. b.p. 69°-72° C./0.3 mmHg

NMR (CDCl₃) δ: 0.81 (6H, t, J=7.1 Hz), 1.26 (3H, t, J=7.2 Hz), 1.61 (4H,q, J=7.2 Hz), 2.07 (2H, t, J=8.6 Hz), 3.45 (2H, t, J=8.6 Hz), 4.15 (2H,q, J=7.1 Hz)

REFERENCE EXAMPLE 19 Production of ethyl 5-bromo-2,2-diethylvalerate

Using ethyl 2-ethylbutyrate and 1,3-dibromopropane, the same reaction asin Reference Example 16 was conducted to produce the title compound.b.p. 98°-102° C./0.3 mmHg

NMR (CDCl₃) δ: 0.79 (6H, t, J=7.4 Hz), 1.25 (3H, t, J=7.0 Hz), 1.51-1.86(8H, m), 3.39 (2H, t, J=6.2 Hz), 4.14 (2H, q, J=7.0 Hz)

REFERENCE EXAMPLE 20 Production of ethyl 6-bromo-2,2-diethylhexanate

Using ethyl 2-ethylbutyrate and 1,4-dibromobutane, the same reaction asin Reference Example 16 was conducted to produce the title compound.b.p. 125°-130° C./0.3 mmHg

NMR (CDCl₃) δ: 0.80 (6H, t, J=7.6 Hz), 1.27 (3H, t, J=7.0 Hz), 1.49-1.78(4H, m), 1.61 (4H, q, J=7.6 Hz), 2.90-3.02 (2H, m), 4.15 (2H, q, J=7.0Hz)

REFERENCE EXAMPLE 21 Production of ethyl2,2-dimethyl-5-thiocyanovalerate

In 120 ml of dimethylformamide were dissolved 40.3 g of the ethyl5-bromo-2,2-dimethylvalerate obtained in Reference Example 16 and 18.2 gof potassium thiocyanate and the mixture was stirred at 85° C. for 5hours. The reaction mixture was then poured in 500 ml of water andextracted with ethyl ether and the extract was washed with water anddried. The solvent was distilled off and the residue was subjected tovacuum distillation to provide 35.7 g of the title compound as oil. b.p.116°-118° C./0.3 mmHg

REFERENCE EXAMPLE 22 Production of ethyl2,2-dimethyl-6-thiocyanohexanoate

Using the ethyl 6-bromo-2,2-dimethylhexanoate obtained in ReferenceExample 17 and potassium thiocyanate, the same reaction as in ReferenceExample 21 was conducted to product the title compound. b.p. 123°-125°C./0.4 mmHg

NMR (CDCl₃) δ: 1.17 (6H, s), 1.25 (3H, t, J=7.2 Hz), 1.33-1.65 (4H, m),1.73-2.08 (2H, m), 2.94 (2H, t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz)

REFERENCE EXAMPLE 23 Production of ethyl 2,2-diethyl-4-thiocyanobutyrate

Using the ethyl 4-chloro-2,2-diethylbutyrate obtained in ReferenceExample 18 and potassium thiocyanate, the same reaction as in ReferenceExample 21 was conducted to product the title compound. b.p. 105°-108°C./0.3 mmHg

NMR (CDCl₃) δ: 0.81 (3H, t, J=7.4 Hz), 0.83 (3H, t, J=7.4 Hz), 1.27 (3H,t, J=7.0 Hz), 1.54-1.72 (4H, m), 2.00-2.13 (2H, m), 2.80-2.92 (2H, m),4.17 (2H, q, J=7.0 Hz)

REFERENCE EXAMPLE 24 Production of ethyl 2,2-diethyl-5-thiocyanovalerate

Using the ethyl 5-bromo-2,2-diethylvalerate obtained in ReferenceExample 19 and potassium thiocyanate, the same reaction as in ReferenceExample 21 was conducted to produce the title compound. b.p. 125°-130°C./0.3 mmHg

NMR (CDCl₃) δ: 0.80 (6H, t, J=7.6 Hz), 1.27 (3H, t, J=7.0 Hz), 1.49-1.78(4H, m), 1.61 (4H, q, J=7.6 Hz), 2.90-3.02 (2H, m), 4.15 (2H, q, J=7.0Hz).

REFERENCE EXAMPLE 25 Production of ethyl2,2-diethyl-6-thiocyanohexanoate

Using the ethyl 6-bromo-2,2-diethylhexanoate obtained in ReferenceExample 20 and potassium thiocyanate, the same reaction as in ReferenceExample 21 was conducted to produce the title compound. b.p. 145°-148°C./0.3 mmHg

NMR (CDCl₃) δ: 0.78 (6H, t, J=7.6 Hz), 1.25 (3H, t, J=7.0 Hz), 1.21-1.68(8H, m), 1.82 (2H, m), 2.95 (2H, t, J=7.4 Hz), 4.14 (2H, q, J=7.0 Hz)

REFERENCE EXAMPLE 26 Production of ethyl5-aminosulfonyl-2,2-dimethylvalerate

In a mixture of 150 ml of acetic acid and 150 ml of water was dissolved35.68 g of the ethyl 2,2-dimethyl-5-thiocyanovalerate obtained inReference Example 21 and while the solution was vigorously stirred,chlorine gas was bubbled through the solution at 10° to 15° C. for 1.2hours. The mixture was further stirred at 0° C. for 1 hour, at the endof which time it was extracted with dichloromethane. The extract waswashed with water and dried and the solvent was distilled off. Theresidue was dissolved in 200 ml of dichloromethane and ammonia gas wasbubbled through the solution at 0° C. for 40 minutes. The insolubleswere filtered off and the filtrate was washed with water and dried. Thesolvent was then distilled off. The residue was subjected to silica gel(150 g) column chromatography and elution was carried out with ethylacetate-hexane (1:1) to provide 30 g of the title compound.

NMR (CDCl₃) δ: 1.20 (6H, s), 1.26 (3H, t, J=7.4 Hz), 1.61-1.93 (4H, m),3.11 (2H, t, J=7.0 Hz), 4.14 (2H, q, J=7.4 Hz), 4.88 (2H, bs)

REFERENCE EXAMPLE 27 Production of ethyl6-aminosulfonyl-2,2-dimethylhexanoate

Using the ethyl 2,2-dimethyl-6-thiohexanoate obtained in ReferenceExample 22, the same reaction as in Reference Example 26 was conductedto produce the title compound.

NMR (CDCl₃) δ: 1.17 (6H, s), 1.25 (3H, t, J=7.2 Hz), 1.32-1.64 (4H, m),1.85 (2H, t, J=7.6 Hz), 3.12 (2H, t, J=7.6 Hz), 4.12 (2H, q, J=7.2 Hz),4.84 (2H, bs)

REFERENCE EXAMPLE 28 Production of ethyl4-aminosulfonyl-2,2-dimethylbutyrate

Using the ethyl 2,2-diethyl-4-thiocyanobutyrate obtained in ReferenceExample 23, the same reaction as in Reference Example 26 was conductedto produce the title compound. m.p. 93°-94° C.

Elemental analysis: for C₁₀ H₂₁ NO₄ S Calcd. (%): C, 47.79; H, 8.42; N,5.57 Found (%): C, 47.73; H, 8.44; N, 5.70

NMR (CDCl₃) δ: 0.83 (6H, t, J=7.4 Hz), 1.27 (3H, t, J=7.0 Hz), 1.61 (4H,q, J=7.4 Hz), 2.03-2.16 (2H, m), 2.99-3.13 (2H, m), 4.17 (2H, q, J=7.0Hz), 4.84 (2H, bs)

REFERENCE EXAMPLE 29 Production of ethyl5-aminosulfonyl-2,2-diethylvalerate

Using the ethyl 2,2-diethyl-5-thiocyanovalerate obtained in ReferenceExample 24, the same reaction as in Reference Example 26 was conductedto produce the title compound. m.p. 66°-67° C.

Elemental analysis for C₁₁ H₂₃ NO₄ S Calcd (%): C, 49.79, H, 8.74; N,5.28 Found (%): C, 49.43; H, 8.81; N, 5.18

NMR (CDCl₃) δ: 0.79 (6H, t, J=7.4 Hz), 1.26 (3H, t, J=7.2 Hz), 1.61 (4H,q, J=7.4 Hz), 1.66-1.85 (4H, m), 3.11 (2H, t, J=6.6 Hz), 4.15 (2H, q,J=7.2 Hz), 4.84 (2H, bs)

REFERENCE EXAMPLE 30 Production of ethyl6-aminosulfonyl-2,2-diethylhexanoate

Using the ethyl 2,2-diethylhexanoate obtained in Reference Example 25,the same reaction as in Reference Example 26 was conducted to producethe title compound.

NMR (CDCl₃) δ: 0.77 (6H, t, J=7.4 Hz), 1.25 (3H, t, J=7.2 Hz), 1.19-1.40(2H, m), 1.58 (4H, q, J=7.4 Hz), 1.49-1.69 (2H, m), 1.85 (2H, m), 3.12(2H, m), 4.13 (2H, q, J=7.2 Hz), 4.71 (2H, bs)

REFERENCE EXAMPLE 31 Production of5-hydroxy-4,4-dimethyl-1-pentanesulfonamide

A solution of 7.1 g of the ethyl 5-aminosulfonyl-2,2-dimethylvalerateobtained in Reference Example 26 in 20 ml of tetrahydrofuran was addeddropwise to a suspension of 1.71 g of lithium aluminum hydride in 100 mlof tetrahydrofuran with ice-cooling and stirring. After completion ofdropwise addition, the mixture was stirred at 0° C. for 40 minutes andafter addition of aqueous tetrahydrofuran for decomposition of excesslithium aluminum hydride, the mixture was neutralized with2N-hydrochloric acid and extracted with ethyl acetate. The extract waswashed with water and dried (MgSO₄) and the solvent was distilled off.The residue was subjected to silica gel (100 g) column chromatographyand elution was carried out with hexane-ethyl acetate (4:1) to provide3.39 g of the title compound as oil.

NMR (CDCl₃) δ: 0.90 (6H s), 1.35-1.50 (2H, m), 1,75-1.97 (2H, m), 3.12(2H, t, J=7.8 Hz), 3.35 (2H, s), 5.04 (2H, bs)

REFERENCE EXAMPLE 32 Production of6-hydroxy-5,5-dimethyl-1-hexanesulfonamide

Using the ethyl 6-aminosulfonyl-2,2-dimethylhexanoate obtained inReference Example 27, the same reaction as in Reference Example 31 wasconducted to produce the title compound.

NMR (CDCl₃) δ: 0.87 (6H, s), 1.21-1.54 (4H, m), 1.76-1.94 (2H, m), 2.05(1H, s), 3.16 (2H, t, J=8 Hz), 3.31 (2H, s), 5.13 (2H, bs)

REFERENCE EXAMPLE 33 Production of4-hydroxy-3,3-diethyl-1-butanesulfonamide

Using the ethyl 4-aminosulfonyl-2,2diethylbutyrate obtained in ReferenceExample 28, substantially the same reaction as in Reference Example 31was conducted to produce the title compound. m.p. 79°-80° C.

Elemental analysis for C₈ H₁₉ NO₃ S Calcd (%): C, 45.91; H, 9.15; N,6.69 Found (%): C, 46.00; H, 9.20; N, 6.69

NMR (CDCl₃) δ: 0.74 (6H, t, J=7.4 Hz), 1.58 (4H, q, J=7.4 Hz), 1.50-1.66(2H, m), 2.83-2.97 (2H, m), 3.11 (2H, s), 6.71 (2H, bs)

REFERENCE EXAMPLE 34 Production of5-hydroxy-4,4-diethyl-1-pentanesulfonamide

Using the ethyl 5-aminosulfonyl-2,2diethylvalerate obtained in ReferenceExample 29, the same reaction as in Reference Example 31 was conductedto produce the title compound.

NMR (CDCl₃) δ: 0.79 (6H, t, J=7.6 Hz), 1.14-1.45 (6H, m), 1.70-1.89 (2H,m), 2.05 (1H, s), 3.12 (2H, t, J=7.6 Hz), 3.39 (2H, s), 5.18 (2H, bs)

REFERENCE EXAMPLE 35 Production of6-hydroxy-5,5-diethyl-1-hexanesulfonamide

Using the ethyl 6-aminosulfonyl-2,2-diethylhexanoate obtained inReference Example 30, the same reaction as in Reference Example 31 wasconducted to produce the title compound. m.p. 64°-65° C.

Elemental analysis for C₁₀ H₂₃ NO₃ S Calcd (%): C, 50.60, H, 9.77; N,5.90 Found (%): C, 50.90; H, 9.58; N, 6.15

NMR (CDCl₃) δ: 0.78 (6H, t, J=7.2 Hz), 1.15-1.49 (4H, m), 1.23 (4H, q,J=7.2 Hz), 1.67 (1H, s), 1.85 (2H, m), 3.15 (2H, t, J=4.6 Hz), 3.35 (2H,s), 4.90 (2H, bs)

REFERENCE EXAMPLE 36 Production of4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-butanol

To a solution of 2.0 g of the 4-hydroxy-3,3-diethyl-1-butanesulfonamideobtained in Reference Example 33 in 30 ml of toluene was added 1.2 g ofN,N-dimethylformamide dimethyl acetal and the mixture was stirred at 90°C. for 1 hour. The solvent was then distilled off under reducedpressure. The residue was subjected to silica gel (70 g) columnchromatograhy and elution was carried out with ethylacetate-chloroform-methanol (20:20:1) to provide 2.43 g of the titlecompound as oil.

NMR (CDCl₃) δ: 0.81 (6H, t, J=7.4 Hz), 1.15-1.38 (4H, m), 1.68-1.80 (2H,m), 1.96 (1H, bs), 2.96-3.07 (2H, m), 3.04 (3H, s), 3.14 (3H, s), 3.36(2H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 37 Production of5-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-pentanol

Using the 5-hydroxy-4,4-diethyl-1-pentanesulfonamide obtained inReference Example 34, the same reaction as in Reference Example 36 wasconducted to produce the title compound. m.p. 87°-88° C.

Elemental analysis for C₁₂ H₂₆ N₂ O₃ S Calcd (%): C, 51.77; H, 9.41; N,10.06 Found (%): C, 51.75; H, 9.47; N, 10.09

NMR (CDCl₃) δ: 0.78 (6H, t, J=7.4 Hz), 1.18-1.41 (6H, m), 1.64 (1H, s),1.70-1.85 (2H, m), 2.99 (2H, t, J=7.6 Hz), 3.04 (3H, s), 3.14 (3H, s),3.37 (2H, s), 8.04 (1H, s)

REFERENCE EXAMPLE 38 Production of 2-isopropyl-1,3-propanediol

To a suspension of 4.17 g of lithium aluminum hydride in tetrahydrofuranwas added 15 g of diethyl isopropyl malonate dropwise with ice-coolingand stirring. After completion of dropwise addition, the reactionmixture was stirred at 0° C. for 30 minutes and, then, at roomtemperature for 1 hour. To this mixture was added aqueous tetrahydrofurnfor decomposing the excess reagent. The mixture was then neutralizedwith 6N-hydrochloric acid and the insolubles were filtered off. Thefiltrate was extracted with ethyl acetate and the extract was washedwith water and dried (MgSO₄). The solvent was then distilled off underreduced pressure to provide 7.47 g of the title compound.

NMR (CDCl₃) δ: 0.92 (3H, s), 0.95 (3H, s), 1.49-1.65 (1H, m), 1.66-1.86(1H, m), 2.32 (2H, bs), 3.72-3.93 (4H, m)

REFERENCE EXAMPLE 39 Production of 2-ethyl-2-methyl-1,3-propanediol

Using diethyl 2-ethyl-2-methylmalonate, the same reaction as inReference Example 38 was conducted to produce the title compound. b.p.78°-81° C./0.3 mmHg

NMR (CDCl₃) δ: 0.81 (3H, s), 0.87 (3H, t, J=7.2 Hz), 1.38 (2H, q, J=7.2Hz), 2.48 (2H, bs), 3.54 (4H, s)

REFERENCE EXAMPLE 40 Production of 3-bromo-2-isopropyl-1-propanol

In 150 ml of dichoromethane was dissolved 11.8 g of the2-isopropyl-1,3-propanediol obtained in Reference Example 38, followedby addition of 26 g of triphenylphosphine. Then, with ice-cooling, 17.8g of N-bromosuccinimide was added in small portions. This reactionmixture was stirred under ice-cooling for 30 minutes and, then, at roomtemperature for 1 hour. The reaction mixture was then concentrated underreduced pressure. The residue was subjected to silica gel (100 g) columnchromatography and elution was carried out with ethyl acetate-hexane(3:7) to provide 11.87 g of the title compound as colorless oil.

NMR (CDCl₃) δ: 0.94 (3H, s), 0.98 (3H, s), 1.40-1.69 (2H, m), 1.71-1.93(1H, m), 3.61-3.92 (4H, m)

REFERENCE EXAMPLE 41 Production of 3-bromo-2-ethyl-2-methyl-1-propanol

Using the 2-ethyl-2-methyl-1,3-propanediol obtained in Reference Example39, the same reaction as in Reference Example 40 was conducted toproduce the title compound.

NMR (CDCl₃) δ: 0.87 (3H, t, J=7.4 Hz), 0.96 (3H, s), 1.40 (2H, q, J=7.4Hz), 1.53 (1H, bs), 3,40 (2H, s), 3.48 (2H, s)

REFERENCE EXAMPLE 42 Production of3-acetoxy-2-isopropyl-1-propanethiocyanate

A mixture of 22 g of 3-bromo-2-isopropyl-1-propanol, 16.5 g of potassiumthiocyanate and 100 ml of dimethylformamide was stirred at 100° C. for15 hours. After cooling, 200 ml of diethyl ether and 200 ml of waterwere added to the reaction mixture and the organic layer was separated.The aqueous layer was extracted with 150 ml of diethyl acetate and theorganic layers were combined, washed with saturated aqueous solution ofsodium chloride and dried. The solvent was distilled off under reducedpressure. To the residue were added 17.4 g of acetic anhydride and 18.3g of pyridine and the mixture was stirred at room temperature for 3hours. The solvent was then distilled off under reduced pressure. Theresidue was subjected to silica gel (200 g) column chromatography andelution was carried out with ethyl acetate-hexane (1:5) to provide 14.07g of the title compound as colorless oil.

NMR (CDCl₃) δ: 0.97 (3H, d, J=7.3 Hz), 1.01 (3H, d, J=7.3 Hz), 1.84-2.05(2H, m), 2.08 (3H, s), 2.97-3.24 (2H, m), 4.03-4.35 (2H, m)

REFERENCE EXAMPLE 43 Production of 3-acetoxy-2-ethyl-2-methyl-1-propanethiocyanate

Using 3-bromo-2-ethyl-2-methyl-1-propanol, the procedure of ReferenceExample 42 was otherwise repeated to provide the title compound.

NMR (CDCl₃) δ: 0.90 (3H, t, J=7.4 Hz), 1.03 (3H, s), 1.46 (2H, q, J=7.4Hz), 2.09 (3H, s), 3.07 (2H, s), 3.94 (2H, s)

REFERENCE EXAMPLE 44 Production of3-acetoxy-2-isopropyl-1-propanesulfonamide

In a mixture of 50 ml of acetic acid and 50 ml of water was dissolved 10g of 3-acetoxy-2-isopropyl-1-propane thiocyanate and while the solutionwas stirred vigorously, chlorine gas was bubbled through the solution atroom temperature for 2 hours. The reaction mixture was extracted withdichloromethane and the extract was washed with saturated aqueoussolution of sodium chloride and dried. The solvent was then distilledoff under reduced pressure. The residue was dissolved in 100 ml ofdichloromethane, and with cooling, ammonia gas was bubbled through thesolution for 30 minutes, with the reaction temperature being controlledbelow 15° C. After the precipitate was filtered off, the filtrate wasconcentrated. The residue was subjected to silica gel (100 g) columnchromatography and elution was carried out with methanol-chloroform(1:20) to provide 7.9 g of the title compound as oil.

NMR (CDCl₃) δ: 0.96 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz), 1.89-2.07(1H, m), 2.08 (3H, s), 2.17-2.32 (1H, m), 3.11-3.19 (2H, m), 4.21-4.29(2H, m), 4.87 (2H, bs)

REFERENCE EXAMPLE 45 Production of3-acetoxy-2-ethyl-2-methyl-1-propanesulfonamide

Using 3-acetoxy-2-ethyl-2-methyl-1-propanethiocyanate, the same reactionas in Reference Example 44 was conducted to produce the title compound.

NMR (CDCl₃) δ: 0.90 (3H, t, J=7.4 Hz), 1.16 (3H, s), 1.57 (2H, q, J=7.4Hz), 2.09 (3H, s), 3.24 (2H, dd, J=2.5 Hz & 4.9 Hz), 4.08 (2H, s), 4.86(2H, bs)

REFERENCE EXAMPLE 46 Production of3-hydroxy-2-isopropyl-1-propanesulfonamide

In 50 ml of methanol was dissolved 7.0 g of3-acetoxy-2-isopropyl-1-propanesulfonamide and while the solution wasstirred at room temperature, 6.5 g of 28 w/w % sodium methoxide wasadded and reacted for 30 minutes. The reaction mixture was thenconcentrated to dryness. The residue was subjected to silica gel (100 g)column chromatography and elution was carried out withchloroform-methanol (9:1) to provide 4.4 g of the title compound. m.p.83°-84° C.

Elemental analysis for C6H₁₅ NO₃ S Calcd (%): C, 39.67; H, 8.34; N, 7.73Found (%): C, 39.72; H, 8.36; N, 7.78

NMR (d₆ -DMSO) δ: 0.87 (3H, d, J=7.0 Hz), 0.87 (3H, d, J=7.0 Hz),1.79-2.09 (2H, m), 2.85-2.95 (2H, m), 3.43-3.59 (2H, m), 4.55 (1H, bs),6.77 (2H, bs)

REFERENCE EXAMPLE 47 Production of3-hydroxy-2-ethyl-2-methyl-1-propanesulfonamide

Using 3-acetoxy-2-ethyl-2-methyl-1-propanesulfonamide, the same reactionas in Reference Example 46 was conducted to produce the title compound.

NMR (CDCl₃) δ: 0.90 (3H, t, J=7.4 Hz), 1.07 (3H, s), 1.33-1.68 (2H, m),2.71 (1H, bs), 3.22 (2H, q, J=7.4 Hz), 3.61 (2H, s), 5.13 (2H, bs)

REFERENCE EXAMPLE 48 Production of ethyl 1-(2-chloroethyl)cyclohexanoate

Using ethyl cyclohexanoate, the same reaction as in Reference Example 1was conducted to produce the title compound. b.p. 83°-86° C./0.25 mmHg

NMR (CDCl₃) δ: 1.11-1.68 (8H, m), 1.27 (3H, t, J=7.2 Hz), 2.01 (2H, t,J=6.7 Hz), 1.91-2.16 (2H, m), 3.45 (2H, t, J=6.7 Hz), 4.16 (2H, q, J=7.2Hz)

REFERENCE EXAMPLE 49 Production of ethyl1-(2thiocyanoethyl)cyclohexnoate

Using ethyl 1-(2-chloroethyl)cyclohexonate, the same reaction as inReference Example 2 was conducted to produce the title compound. b.p.118°-122° C./0.25 mmHg

NMR (CDCl₃) δ: 1.29 (3H, t, J=7.2 Hz), 1.14-1.66 (8H, m), 1.92-2.14 (4H,m), 2.80-2.90 (2H, m), 4.19 (2H, q, J=7.2 Hz)

REFERENCE EXAMPLE 50 Production of ethyl1-(2-aminosulfonylethyl)cyclohexanoate

Using ethyl 1-(2-thiocyanoethyl)cyclohexanoate, the same reaction as inReference Example 3 was conducted to produce the title compound.

NMR (CDCl₃) δ: 1.27 (3H, t, J=7.0 Hz), 1.16-1.71 (10 H, m), 1.94-2.14(2H, m), 2.98-3.13 (2H, m), 4.17 (2H, q, J=7.0 Hz), 4.69 (2H, bs)

REFERENCE EXAMPLE 51 Production of4-hydroxy-3,3-pentamethylene-1-butanesulfonamide

Using ethyl 1-(2-aminosulfonylethyl)cyclohexanoate, the same reaction asin Reference Example 4 was conducted to produce the title compound.

NMR (CDCl₃) δ: 1.19-1.56 (10H, m), 1.82-1.97 (2H, m), 2.05 (1H, s),3.06-3.22 (2H, m), 3.43 (2H, s), 5.27 (2H, bs)

REFERENCE EXAMPLE 52 Production of3-(N,N-dimethylaminomethylene)aminosulfonyl-2-isopropyl-1-propanol

Using 3-hydroxy-2-isopropyl-1-propanesulfonamide, the same reaction asin Reference Example 5 was conducted to produce the title compound.

NMR (CDCl₃) δ: 0.91 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 1.64 (1H,bs), 1.82-2.11 (2H, m), 3.04 (3H, s), 3.11 (2H, d, J=6.6 Hz), 3.15 (3H,s), 3.63-3.93 (2H, m), 8.06 (1H, s)

REFERENCE EXAMPLE 53 Production of3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanol

Using 3-hydroxy-2-ethyl-2-methyl-1-propanesulfonamide, the same reactionas in Reference Example 5 was conducted to produce the title compound.

NMR (CDCl₃) δ: 0.88 (3H, t, J=7.4 Hz), 1.05 (3H, s), 1.32-1.73 (2H, m),3.04 (2H, q, J=7.4 Hz), 3.05 (3H, s), 3.15 (3H, s), 3.56-3.69 (2H, m),8.05 (1H, s)

REFERENCE EXAMPLE 54 Production of4-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-pentamethylene-1-butanol

Using 4-hydroxy-3,3-pentamethylene-1-butanesulfonamide, the samereaction as in Reference Example 5 was conducted to produce the titlecompound.

NMR (CDCl₃) δ: 1.22-1.54 (10H, m), 1.80-1.94 (4H, m), 3.05 (3H, s), 3.14(3H, s), 3.41 (2H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 55 Production ofN,N-dimethyl-3-hydroxypropane-1-sulfonamide

Using 3-acetoxypropane-1-sulfonyl chloride and dimethylaminehydrochloride, the same reaction as in Reference Example 44 and 46 wasconducted to produce the title compound.

NMR (CDCl₃) δ: 1.91 (1H, bS), 2.0-2.2 (2H, m), 2.89 (6H, s), 3.0-3.2(2H, m), 3.7-3.9 (2H, m).

REFERENCE EXAMPLE 56 Production of3-(1-methyl-4-piperazinylsulfonyl)-1-propanol

Using 3-acetoxypropane-1-sulfonyl chloride and 1-methylpiperazine, thesame reaction as in Reference Example 44 and 46 was conducted to producethe title compound. m.p. 90°-93° C.

Elemental analysis for C₈ H₁₈ N₂ O₃ S Calcd. (%): C, 43.22; H, 8.16; N,12.60 Found. (%) : C, 43.01; H, 8.20; N, 12.53

FORMULATION EXAMPLE 1

(1) Compound of Example 1 10.0 mg

(2) Lactose 60.0 mg

(3) Corn starch 35.0 mg

(4) Gelatin 3.0 mg

(5) Magnesium stearate 2.0 mg

Using 0.03 ml of a 10% aqueous solution of gelatin (3.0 mg as gelatin),a mixture of 10.0 mg of the compound of Example 1, 60.0 mg of lactoseand 35.0 mg of corn starch was granulated by passage through a 1 mm-meshsieve, dried at 40° C. and re-sieved. The resulting granules wereblended with 2.0 mg of magnesium stearate and the blend wascompression-molded. The resulting core tablet was sugar-coated with anaqueous suspension containing sucrose, titanium dioxide, talc and gumarabic. The thus-coated tablet was polished with beeswax to provide acoated tablet.

FORMULATION EXAMPLE 2

(1) Compound of Example 1 10.0 mg

(2) Lactose 70.0 mg

(3) Corn starch 50.0 mg

(4) Soluble starch 7.0 mg

(5) Magnesium stearate 3.0 mg

Using 0.07 ml of an aqueous solution of soluble starch (7.0 mg assoluble starch), a mixture of the compound of Example 1 and 3.0 mg ofmagnesium stearate was granulated, dried and blended with 70.0 g oflactose and 50.0 mg of corn starch. The mixture was compression-moldedto provide a tablet.

FORMULATION EXAMPLE 3

(1) Compound of Example 1 5.0 mg

(2) Sodium chloride 20.0 mg

(3) Distilled water 2 ml

First, 5.0 mg of the compound obtained in Example 1 and 20.0 mg ofsodium chloride were dissolved in distilled water and the solution wasdiluted with water to make 2.0 ml. The solution was filtered andaseptically filled into a 2 ml-ampul. The ampul was sterilized andsealed to provide an injectable solution.

EXPERIMENT

The results of a pharmacological test of the compound [I] or saltthereof according to the invention are shown below. [Effect on plateletactivating factor (PAF)-induced guinea pig bronchoconstriction]

Male Hartley guinea pigs (body weights about 500 g) were used.Bronchoconstriction induced by PAF, 1 μg/kg i.v., in guinea pigs wasmeasured using to the method of Konzett-Roessler. With the guinea pigimmobilized in the dorsal position, tracheotomy was performed underurethane (1.5 g/kg i.v.) anesthesia and the trachea was connectedthrough a cannula to a respirator. The side branch of the trachealcannula was connected to a transducer (Model 7020, Ugobasile). With thevolume of air per feed being controlled at 3-7 ml, the ventilationfrequency at 70/min. and the pulmonary loading pressure at 10 cm H₂ O,the volume of overflow air was recorded on a rectigraph (Recte-Hori-8s,San-ei Sokki) through the transducer. After administration of gallamine(1 mg/kg i.v.), PAF, 1 μg/kg, dissolved in physiological saline wasadministered through a jugular vein cannula and the inducedbronchoconstriction was recorded for 15 minutes. The drug suspended in a5% solution of gum arabic was administered orally in a dose of 30 mg/kgor 10 mg/kg one hour before PAF treatment. The results are presented inTable 1.

                  TABLE 1                                                         ______________________________________                                        Effect on PAF-induced bronchoconstriction in                                  guinea pigs                                                                               % Inhibition of PAF-induced                                       Example     bronchoconstriction                                               No.         30 mg/kg, p.o.                                                                            10 mg/kg, p.o.                                        ______________________________________                                        1           59          --                                                    2           57          --                                                    3           65          43                                                    4           --          45                                                    5           --          72                                                    7           --          51                                                    10          --          75                                                    11          --          77                                                    12          --          61                                                    ______________________________________                                    

It will be apparent from Table 1 that the compound [I] or a salt thereofof the invention have excellent anti-PAF (platelet activating factor)activity. [Effect on leukotriene C₄ (LTC₄)-induced guinea pigbronchoconstriction]

Male Hartley guinea pigs (body weights about 500 g) were used.Bronchoconstriction induced by LTC₄, 20 μg/kg i.v., in guinea pigs wasmeasured using to the method of Konzett-Rossler. With the guinea pigimmobilized in the dorsal position, tracheotomy was performed underurethane (1.5 g/kg i.v.) anesthesia and the trachea was connectedthrough a cannula to a respirator. The side branch of the trachealcannula was connected to a transducer (Model 7020, Ugobasile). With thevolume of air per feed being controlled at 3-7 ml, the ventilationfrequency at 70/min. and the pulmonary loading pressure at 10 cm H₂ O,the volume of overflow air was recorded on a rectigraph (Recte-Hori-8s,San-ei Sokki) through the transducer. After administration of gallamine(1 mg/kg i.v.), LTC₄, 20 μg/kg, dissolved in physiological saline wasadministered through a jagular vein cannula and the inducedbronchoconstriction was recorded for 15 minutes. The drug suspended in a5% solution of gum arabic was administered orally one hour before LTC₄treatment. The results are presented in Table 2.

                  TABLE 2                                                         ______________________________________                                        Effect on LTC.sub.4 - induced bronchoconstriction                             in guinea pigs.                                                                                          % Increase in                                              Dose      No. of   respiratory                                                                             %                                                (mg/kg)   animals  airflow   Inhibition                               ______________________________________                                        Control --        6        58.4 ± 1.1                                                                           --                                       Example 1         6        43.9 ± 4.8*                                                                          25                                       No. 5   3         6        26.7 ± 4.3**                                                                         54                                               10        6        18.9 ± 3.8**                                                                         68                                       ______________________________________                                         *P < 0.05,                                                                    **P < 0.01 vs control                                                    

It will be apparent from Table 2 that the compound [I] or a salt thereofof the invention have excellent anti-LTC₄ (leukotriene C₄) activity.[Effect on endothelin-1 (ET-1)-induced guinea pig bronchoconstriction]

Male Hartley guinea pugs (body weights about 500 g) were used.Bronchoconstriction induced by ET-1, 5 μg/kg i.v., in guinea pigs wasmeasured using to the method of Konzett-Rossler. With the guinea pigimmobilized in the dorsal position, tracheotomy was performed underurethane (1.5 g/kg i.v.) anesthesia and the trachea was connectedthrough a cannula to a respirator. The side branch of the trachealcannula was connected to a transducer (Model 7020, Ugobasile). With thevolume of air per feed being controlled at 3-7 ml, the ventilationfrequency at 70/min. and the pulmonary loading pressure at 10 cm H₂ O,the volume of overflow air was recorded on a rectigraph (Recte-Hori-8s,San-ei Sokki) through the transducer. After administration of gallamine(1 mg/kg i.v.), ET-1, 5 μg/kg, dissolved in physiological saline wasadministered through a jagular vein cannula and the inducedbronchoconstriction was recorded for 15 minutes. The drug suspended in a5% solution of gum arbic was administrered orally one hour before ET-1treatment. The results are presented in Table 3.

                  TABLE 3                                                         ______________________________________                                        Effect on endothelin-1 (ET-1)- induced                                        bronchoconstriction in guinea pigs.                                                                     % Increase in                                              Dose      No. of   respiratory                                                                              %                                               (mg/kg)   animals  airflow    Inhibition                               ______________________________________                                        Control                                                                              --        6        49.5 ± 5.5                                                                            --                                       Example                                                                              1         6        32.6 ± 7.4                                                                            34                                       No. 5  3         6         19.1 ± 3.8**                                                                         61                                              10        6          7.2 ± 1.0**                                                                         86                                       ______________________________________                                         **P < 0.01 vs control                                                    

It will be apparent from Table 3 that the compound [I] or a salt thereofof the invention have excellent anti-ET-1 (endothelin-1) activity.

What is claimed is:
 1. A compound of the formula: ##STR30## wherein R¹ stands for (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen or (iii) a halogen atom;R² and R³ independently stand for stand for a hydrogen atom or a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen; X stands for an oxygen atom or S(O)_(p), wherein p is a whole number of from 0 to 2; Y stands for (i) a group of the formula: ##STR31## wherein R⁴ and R⁵ independently stand for a hydrogen atom or a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen or (ii) a divalent homocyclic or heterocyclic ring selected from the group consisting of ##STR32## which may be substituted with 1 to 5 substituents selected from the group consisting of a C₁₋₆ alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen, an amino group which may be substituted with 1 or 2 substituents selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ acyl, pyrrolidino, morpholino, piperidino and piperazino, a hydroxy, a carboxyl, a nitro, a C₁₋₆ alkoxy, and a halogen; R⁶ and R⁷ each stands for (i) a hydrogen, (ii) a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen, (iii) a C₃₋₆ cycloalkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen, (iv) a C₆₋₁₄ aryl group which may be substituted with one to five substituents selected from the group consisting of a C₁₋₆ alkyl which may be substituted with one to four substituents selected from the group consisting of hydroxy, amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen, an amino which can be substituted with one or two substituents selected from the group consisting of C₁₋₆ alkyl, pyrrolidino, morpholino, piperidino and piperazino, an acetamido, a hydroxy, a carboxyl, a nitro, a C₁₋₆ alkoxy, a C₁₋₆ alkylcarbonyloxy and a halogen, or (v) R⁶ and R⁷ taken together with the adjacent nitrogen atom form a nitrogen-containing heterocyclic ring selected from the group consisting of ##STR33## which may be substituted with 1 to 5 substituents selected from the group consisting of a C₁₋₆ alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyloxy, and halogen, an amino group which may be substituted with 1 or 2 substituents selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ acyl, pyrrolidino, morpholino, piperidino and piperazino, a hydroxy, a carboxyl, a nitro, a C₁₋₆ alkoxy and a halogen; m stands for a whole number of from 0 to 4; n stands for a whole number of from 0 to 4; or a pharmaceutically acceptable salt thereof.
 2. A compound as claimed in claim 1, wherein the divalent group derived from a 3- to 7-membered homocyclic ring stands for a group of the formula: ##STR34##
 3. A compound as claimed in claim 1, wherein the divalent group derived from a 3- to 7-membered heterocyclic ring stands for a group of the formula: ##STR35##
 4. A compound as claimed in claim 1, wherein the nitrogen-containing heterocyclic group stands for a group of the formula: ##STR36##
 5. A compound as claimed in claim 1, wherein R¹ stands for a hydrogen atom or a C₁₋₃ alkyl group.
 6. A compound as claimed in claim 1, wherein R² and R³ independently stand for a hydrogen atom.
 7. A compound as claimed in claim 1, wherein Y stands for (i) a group of the formula: ##STR37## (R^(4') and R^(5') independently stand for a hydrogen atom or a C₁₋₃ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen) or (ii) a group of the formula: ##STR38##
 8. A compound as claimed in claim 1, wherein R⁶ and R⁷ respectively stand for a hydrogen atom or a C₁₋₃ alkyl group.
 9. A compound as claimed in claim 1, wherein X stands for an oxygen atom.
 10. A compound as claimed in claim 1, wherein R¹, R², and R³ independently stand for a hydrogen atom or a C₁₋₃ alkyl group; Y stands for (i) a group of the formula: ##STR39## (R^(4") and R^(5") independently stand for a hydrogen atom or a C₁₋₃ alkyl group) or (ii) a group of the formula: ##STR40## R⁶ and R⁷ independently stand for (i) a hydrogen atom or (ii) a C₁₋₃ alkyl group, or (iii) they can, taken together with the adjacent nitrogen atom, form a group of the formula: ##STR41## which is optionally substituted with 1 to 5 substituents selected from the group consisting of a C₁₋₆ alkyl group which can be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy, and halogen, an amino group which can be substituted with 1 or 2 substituents selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ acyl, pyrrolidino, morpholino, piperidino and piperazino, a hydroxy, a carboxyl, a nitro, a C₁₋₆ alkoxy and a halogen; X stands for an oxygen or sulfur atom; m stands for a whole number of 1 to 3; and n stands for a whole number of 1 to
 4. 11. A compound as claimed in claim 1, wherein R¹, R² and R³ independently stand for a hydrogen atom or a C₁₋₃ alkyl group; Y stands for (i) group of the formula: ##STR42## (R^(4") and R^(5") respectively stand for a hydrogen atom or a C₁₋₃ alkyl group) or (ii) a group of the formula: ##STR43## R⁶ and R⁷ respectively stand for a hydrogen atom or a C₁₋₃ alkyl group; X stands for an oxygen atom; m stands for a whole number of 1 to 3; and n stands for a whole number of 1 to
 4. 12. A compound as claimed in claim 1, wherein R¹ and R² both are a hydrogen atom; R³ is a C₁₋₃ alkyl group; Y stands for (i) a group of the formula: ##STR44## (R^(4'") and R^(5'") stand for a C₁₋₃ alkyl group) or (i) a group of the formula: ##STR45## R⁶ and R⁷ both are a hydrogen atom; X stands for a oxygen atom; m is 1; and n is a whole number of 1 to
 4. 13. A compound as claimed in claim 1, wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ respectively stand for a hydrogen atom or a C₁₋₃ alkyl group; X stands for an oxygen atom; m is 1; and n is a whole number of 1 to
 4. 14. A compound as claimed in claim 1, wherein R¹, R², R³, R⁴, and R⁵ respectively stand for a hydrogen atom or a C₁₋₃ alkyl group; and ##STR46## stands for a group of the formula: ##STR47## which may be substituted with one to five substituents selected from the group consisting of an optionally substituted C₁₋₆ alkyl, optionally substituted amino, hydroxy, carboxyl, nitro, C₁₋₆ alkoxy and halogen.
 15. A compound as claimed in claim 1, wherein R¹, R², R³, R⁶ and R⁷ stand for a hydrogen atom; R⁴ and R⁵ independently stand for a C₁₋₃ alkyl group; X stands for an oxygen atom; and m and n both are
 1. 16. A compound as claimed in claim 1, which is 6-(2,2-diethyl-3-sulfamoyl-1-propoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine.
 17. A compound as claimed in claim 1, which is 6-(2,2-diethyl-6-sulfamoyl-1-hexyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine.
 18. A compound as claimed in claim 1, which is 6-(2,2-diethyl-5-sulfamoyl-1-pentyloxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine.
 19. A compound as claimed in claim 1, which is 6-(2,2-diethyl-4-sulfamoyl-1-butoxy)-7-methyl[1,2,4]triazolo[1,5-b]pyridazine.
 20. A compound of the formula: ##STR48## wherein W stands for a halogen, C₆₋₁₀ arylsulfonyloxy, or C₁₋₄ alkylsulfonyloxy;R¹ stands for (i) a hydrogen atom, (ii) a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen or (iii) a halogen atom; R² and R³ independently stand for stand for a hydrogen atom or a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen; X stands for an oxygen atom or S(O)_(p), wherein p is a whole number of from 0 to 2; Y stands for (i) a group of the formula: ##STR49## wherein R⁴ and R⁵ independently stand for a hydrogen atom or a C₁₋₆ alkyl group which may be substituted with one to four substituents selected from the group consisting of a hydroxy, amino, carboxyl, nitro, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen or (ii) a divalent homocyclic or heterocyclic ring selected from the group consisting of ##STR50## which may be substituted with 1 to 5 substituents selected from the group consisting of a C₁₋₆ alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxy, C₁₋₆ alkyl-carbonyloxy and halogen, an amino group which may be substituted with 1 or 2 substituents selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ acyl, pyrrolidino, morpholino, piperidino and piperazino, a hydroxy, a carboxyl, a nitro, a C₁₋₆ alkoxy, and a halogen; m is a whole number from 0 to 4 and n is a whole number from 0 to 4, or a pharmaceutically acceptable salt thereof.
 21. An anti-asthmatic composition, a bronchoconstriction inhibitor or an anti-allergenic composition which comprises an effective amount of a compound as defined in claim 1 and a physiologically acceptable carrier.
 22. A method for treating asthma in mammals which comprises administrating to a subject suffering therefrom an effective amount of a compound as claimed in claim 1 with a physiologically acceptable carrier.
 23. A method for suppressing bronchismus or bronchoconstriction in mammals which comprises administrating to a subject suffering therefrom an effective amount of a compound as claimed in claim 1 with a physiologically acceptable carrier. 